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Why does venlafaxine have lower incidence of sexual dysfunctions at higher doses?

Why does venlafaxine have lower incidence of sexual dysfunctions at higher doses?


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Venlafaxine at low dosages strongly inhibits serotonin, at moderate dosages also norepinephrine and only high dosages it also inhibits dopamine.

The ratio is the following.

  • serotonin : norepinephrine : dopamine
  • 1 : 30 : 93

According to the FDA data these are the percentages for side effects.

  • Libido decreased
  • Placebo 75mg 225mg 375mg
  • 1.1% 2.2% 1.1% 5.7%

Here are the results for other sexual dysfunctions.

  • Abnormal ejaculation/orgasm
  • Placebo 75mg 225mg 375mg
  • 0.0% 4.5% 2.2% 12.5%

and

  • Impotence
  • Placebo 75mg 225mg 375mg
  • 0.0% 5.8% 2.1% 3.6%

How would you explain the sudden drop of sexual dysfunctions at 225mg?

Other questions to consider:

  • Would a lower dose (37.5mg or 25mg) have sexual side effects (SSE) similar to placebo?
  • What dose has the lowest rate of SSE?
  • What is the lowest effective dose with reasonably low SSE?
  • How would adding of NDRI (bupropione) influence SSE given an increased dosage of venlafaxine? (i.e. Could one afford higher doses of venlafaxine with few SSE provided bupropion is taken concomittantly?)

ASSESSMENT OF PATIENTS WITH SEXUAL DYSFUNCTIONS

Evaluation of any patient with sexual dysfunction requires thorough understanding about the type of sexual dysfunction, factors associated with or contributing to sexual dysfunction and factors maintaining the sexual dysfunction. Accordingly, proper evaluation includes detailed history taking (sexual, medical and psychosocial), focused physical examination, laboratory tests (routine and specific) and consultation with appropriate specialists. Careful attention always be paid to the presence of significance comorbidities or underlying etiologies (e.g., cardiovascular disease, diabetes, depression).

Important aspects of evaluation of patients with sexual dysfunctions

Discussing sex-related issues can be embarrassing both for the clinician and the patient. Patients often carry the feeling of failure or that they are abnormal. Clinicians should anticipate the embarrassment of patient and acknowledge that it could be difficult talking about such issues. For example, the clinician may say, “Most people find it difficult to talk about these things and may feel a bit embarrassed. I𠆝 just like to reassure you that everything you say is confidential and that I𠆝 like to help you if I can. The first step is to find out exactly what's going on so that we can figure out how to make things right again. Please feel free to be open with me and to ask questions whenever you have any doubt.” Some of the other important issues for evaluation are given in Table-3 .

Table 3

Important aspects in evaluation of sexual dysfunctions

The basic principles of sexual history taking are given in table-4 . The patient needs to be asked to describe their problem in terms of time and manner of onset, its course over the period, its current status, and associated medical or psychological problems. While taking history, attention must be given to features which can help in distinguishing predominantly psychogenic from predominantly organic sexual dysfunctions ( Table-5 ). But, it is important to note that, in many cases, organic and psychogenic factors may coexist, particularly in individuals or couples with long-standing or chronic sexual dysfunction. In such cases, clinicians need to assess the independent and interactive role of both organic and psychogenic factors.

Table 4

History taking for sexual disorders

Table 5

Differentiating features between psychogenic and organic sexual dysfunction

An important aspect of sexual history taking in females is to remember that women play different roles at different times in their life. Many women have several roles-the professional or worker, housewife, mother, daughter, friend, and lover. It is often seen that the over the years as the demands of other roles increase, lover role fades away. Paying attention to these issues can be very useful, and this information can be collected by using a process called the “timetable of life.” Both partners can be asked to fill in a timetable representing a typical week from their initial interaction to the time of presentation. Various aspects which can be covered during the assessment of a week during a typical time frame may include, family time (that is, with children and partners), work time (both at work and work in the house), extended family time (with parents and relations), social time, personal time, and relationship time (time spent together as a couple). The relationship time must also include information about the sexual activity. A timetable almost always brings forward various elements missing in the relationship and personal time. Repeating the “timetable” for different times in life and comparing it during courtship, when sexual desire was probably good, with the timetable for a time when sexual desire was low is useful and can show how priorities change and how this influences desire for sexual activity. Looking at what happens in a sexual situation often gives much information about the defenses used when a patient engages in sexual activity. Clinician may also note what turns a patient on and off, how engorged he/she becomes in the sexual experience, and whether loss of desire occurs every time or it is situational. Other important aspects which can enhance the understanding about the problem include sexual fantasy, masturbation, genital functioning, and contraception.

Psychosocial history: Psychological factors associated with sexual dysfunction can be divided into three categories: predisposing factors, precipitating factors, and maintaining factors (See table-6 ), which can co-exist with each other. The areas to be explored in psychosocial history are enlisted in table-7 . It is to be remembered that the existence of an organic disease does not rule out the possibility of a coexisting psychogenic factor. Conversely, the presence of psychogenic conditions, such as anxiety, anger, guilt, or marital discord, need not be considered as evidence for a sole primary causation.

Table 6

Psychological factors associated with sexual dysfunctions

Table 7

Psychosocial assessment of sexual dysfunctions

The current psychological state need to be assessed with special focus on symptoms of anxiety or depression, low self-esteem and coping skills, previous and current partner relationships, history of sexual trauma/abuse, occupational and social stresses, socioeconomic status, and educational level. Sexual dysfunction may affect the patient's self-esteem and coping ability, as well as his or her social relationships and occupational performance. These aspects need to be assessed in each case. Clinicians need not assume that every patient is involved in a monogamous, heterosexual relationship.

Considering the fact that sexual problems arise in the interpersonal context, the clinician need to carefully assess past and present partner relationships. Another important aspect of psychosexual history is inquiring specifically about the quality of the relationship between the couple with respect to nonsexual factors, i.e., how to they get along on most issues, communication patterns, gender equality/inequality, level of commitment, dealing with stress, etc. While interviewing the couple together it is important to note the dynamics between the partners. Relationship problems may be due to intrinsic differences between the two, and expectations about sexual fulfillment may also vary. Many a times, lack of proper communication between the couple, which may be due to embarrassment, may be mistaken as lack of caring.

Another important aspect of psychosocial evaluation is the identification of patient/couple needs, expectations from each other, priorities and treatment preferences. These may be significantly influenced by cultural, social, ethnic and religious perspectives. Patient education about the problem is also important in enhancing therapeutic relationship, communication between patient and physician and ensuring patient compliance. Partner involvement is important. On the first visit, it is not always possible to involve the partner but efforts need to be made to involve the patient's partner early in the treatment process at the earliest. If the psychosocial assessment reveals the presence of significant psychological distress or conflict between the couple, further evaluation and management may be carried out either prior to, or along with treatment of sexual dysfunction.

Medical history: Historical events related to the presence of chronic disease, use of pharmacological agents, endocrine disorders, prior surgeries and trauma is to be carefully evaluated. While evaluating women careful medical history is to be obtained about any health problem that might affect sexual anatomy, the vascular system, the neurological system, and the endocrine system. Indirect causes i.e., factors that cause chronic pain, fatigue, and malaise may also contribute to dyspareunia.

Substance use History: Excessive use of alcohol or use of other recreational drugs may cause sexual dysfunction, either by a direct effect on the penile neurovascular system or by causing increased secretion of prolactin, reduction in production of testosterone, or both.

Treatment/Medication History: Clinicians should also enquire about the medication intake, including prescription drugs, over the counter medications and culturally sanctioned aphrodisiacs. Medications commonly associated with sexual dysfunction include diuretics (thiazides, spironolactone), sympatholytics agents (Central agents like methyldopa, clonidine and peripheral agents like reserpine), alpha blockers, beta blockers (particularly nonselective agents), angiotensin-converting enzyme inhibitors, calcium channel blockers, antipsychotics, antidepressants, benzodiazepines, buspirone, lithium, disulfiram, digoxin, histamine H2-receptor blockers, ketoconazole, niacin, phenobarbital, phenytoin, allopurinol, gemfibrozil, clofiberate, phenobarbital, phenytoin, danazol, GnRH agonists, oral contraceptives etc.

Physical Examination

Every effort be made to ensure the privacy, confidentiality and personal comfort of the patient while conducting the physical examination. Careful physical examination not only corroborates the medical history but at times also reveals unsuspected physical findings (e.g., decreased peripheral pulses, vaginal atrophy, atrophic testes, penile plaque).

In addition, to the general and systemic evaluations, detailed assessment of gonadal function, vascular competence, neurological integrity, and genital organ normalcy is to be performed on every patient. Patients suspected of hypogonadism need to be assessed for evidence of muscle development, size and structure of the penis, normal urethral opening, hypospadias, size and consistency of the testes and the prostate. Alcohol swabs can be used to test penile temperature sensation. Bulbo-cavernosus reflex can be elicited by squeezing the glans penis and assessing the evoked contractions of external anal sphincter or bulbo-cavernosus muscles. This reflex response is clinically detectable in 70% of normal males. The penis also needs to be examined for evidence of any masses or plaque formation, angulation, unprovoked persistent erection, or tight unretractable foreskin.

Similarly in females genital examination is often highly informative, especially in cases of dyspareunia, vaginismus, with a history of pelvic trauma and with any disease potentially affecting genital health. If there are indications from history, the opportunity for pap smear/sexually transmitted disease investigation is to be taken.

Recommended Laboratory Testing

Recommended laboratory tests for men and women with sexual problems typically include blood glucose levels, cholesterol, lipids, hormonal profile and X-ray spine for spina bifida. Additional laboratory tests (e.g., thyroid function) may be performed at the discretion of the clinician, based on the medical history and clinician's judgment. When an infective etiology for dyspareunia remains a possibility- vaginal, cervical and vulval discharge microscopy/cultures need to be performed.

Assessment of Knowledge and Attitude towards sex

Few patients may not actually have sexual dysfunction, but may perceive the same, because of poor knowledge and negativistic attitude towards sex. Further, in some patients the sexual problems may be attributed to the beliefs and cultural practices. Some of the scales like Sexual Knowledge and Attitude Questionnaire and Dhat syndrome Questionnaire, which have been validated in the Indian context, may be used for structured assessment and documentation. These scales can also help in determining the area to be focused in sex education and psychoeducation.

Specialist Consultation and Referral

Patients with history of medical problems be referred to appropriate specialty to evaluate the severity and state of disease control (See table-8 ). Sometimes there may not be a need for referral, but if patient requests for the same, it is to be done. Further diagnostic evaluation also needs to be conducted in case of lifelong or primary sexual dysfunction, in the presence of specific anatomic or endocrine factors and failure of initial therapy. Patients with hyposexual desire and absent or retarded emission or anorgasmia may need to be evaluated for the presence of diseases involving the nervous system. Patients with prolonged or painful erection need to be evaluated for the possibility of primary penile disease, hematological disorder, or other systemic diseases associated with penile complication.

Table 8

Medical history, physical examination and investigations for sexual dysfunctions

By the end of assessment the clinician should be able to answer the following questions for themselves to plan management:

Does patient/couple actually have sexual dysfunction?

Whether the dysfunction is primarily psychogenic or primarily organic?

If the dysfunction has organic etiology, then is there a psychological overlay too?

If there are more than one dysfunction, then which is the primary?

Does patient has any comorbid psychiatric disorder?

If subject has a psychiatric disorder, then is the sexual dysfunction secondary to it?

If subject has a psychiatric disorder, then how severe it is?

Is there a marital discord between the couple, which needs to be addressed?

What is the motivation of the patient/couple to seek treatment?

What is the level of psychological sophistication?


Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data

Michelle D. Colvard Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data. Mental Health Clinician 1 January 2014 4 (1): 35–39. doi: https://doi.org/10.9740/mhc.n186977

Venlafaxine XR and its major active metabolite, desvenlafaxine, are serotonin-norepinephrine reuptake inhibitors. Both are FDA-approved for the treatment of major depressive disorder and have essentially the same pharmacologic and pharmacokinetic profiles however, the recommended dosing is notably different. The FDA approved recommended starting and maintenance dose for desvenlafaxine is 50 mg daily, while venlafaxine XR requires titration from 37.5 mg daily to the maintenance dose of 150 - 225 mg daily. The dose recommendation for desvenlafaxine is based on results from 8-week acute-phase clinical trials, but complete therapeutic response is not always achieved in this short time period. Venlafaxine XR relies on CYP2D6 for conversion to desvenlafaxine while desvenlafaxine has no significant metabolism by CYP2D6 at recommended doses. Both venlafaxine XR and desvenlafaxine have limited clinically significant drug interactions. The most striking difference between the two products is cost.

Venlafaxine extended release (XR) was the first once daily serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD) by the Food and Drug Administration (FDA) in 1997. 1 Approximately ten years later desvenlafaxine (O-desmethylvenlafaxine), the primary major active metabolite of venlafaxine, also joined the market for this indication in the form of desvenlafaxine succinate (Pristiq ® ). 2 The FDA also recently approved generic desvenlafaxine fumarate and the free base form of desvenlafaxine as both a generic and brand name (Khedezla ER) products. 3–5 This review will focus on desvenlafaxine succinate as efficacy, pharmacokinetic, and safety data are mostly available for this product.

Venlafaxine and desvenlafaxine are essentially pharmacologically equivalent. 6 , 10 Both are potent and selective inhibitors at serotonin and norepinephrine transporters with small differences in binding affinity measured by Ki value (lower Ki value indicates more selective binding). 2 , 6–8 The Ki values for serotonin reuptake pumps are 40.2 nM and 82 nM for desvenlafaxine and venlafaxine, respectively. 7 , 8 Ki values for norepinephrine reuptake pumps are 558.4 nM and 2480 nM for desvenlafaxine and venlafaxine, respectively. 7 , 8 Theoretically, higher binding affinity for desvenlafaxine versus venlafaxine at norepinephrine reuptake pumps could translate into differences in efficacy but this has not been validated in head-to-head clinical trials. Neither agent has significant affinity for cholinergic, alpha-adrenergic, or histaminergic receptors. 2 , 6 No clinically significant differences in adverse effects or tolerability have been identified in clinical trials. A detailed comparison of adverse effects and tolerability among SNRIs was recently published by Alipour. 9

While there may be subtle variances in receptor binding affinity and adverse effects, more notable differences between the two medications are related to metabolism and FDA approved dosage. 2 , 6 Because venlafaxine is primarily metabolized by cytochrome P450 (CYP) 2D6, there is concern that alterations in CYP2D6 activity could negatively impact efficacy and tolerability. 6 For this reason, it has been speculated that desvenlafaxine may be preferred in patients with drug-drug interactions and genetic polymorphisms which affect CYP2D6. 11–17 Furthermore, the fact that desvenlafaxine has the same starting and maintenance dose while venlafaxine XR should be gradually titrated may make desvenlafaxine a more appealing choice for some providers and patients. 2 , 6 The clinical impact of these differences has not been fully described. This article will review the data related to differences in metabolism and dosing between venlafaxine XR and desvenlafaxine to describe clinical significance.

Pharmacokinetic Comparison

At least 92% of a single dose of venlafaxine XR is absorbed and subsequently undergoes presystemic hepatic metabolism. It is estimated that 55% of a single dose is converted to desvenlafaxine via CYP2D6-mediated phase I oxidative metabolism. CYP1A2, CYP3A4, and CYP2C19 are responsible for the formation of other minor inactive oxidative metabolites including N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. 6 Unlike venlafaxine, desvenlafaxine is primarily inactivated via phase II glucuronidation with minimal oxidative metabolism via CYP3A4 to N,O-didesmethylvenlafaxine. 2 Both venlafaxine XR and desvenlafaxine are primarily renally eliminated as varying concentrations of unchanged drug, active, and inactive metabolites. 2 , 6 Because venlafaxine XR relies on CYP2D6 for conversion to the major active metabolite, there has been much investigation of the differences in its pharmacokinetic parameters and clinical efficacy among patients with CYP2D6 polymorphisms (polymorphisms in the CYP2D6 gene can result in phenotypes with varying levels of metabolic activity). 6 Extensive (EM) and intermediate metabolizers (IM) are considered to have ‘normal' levels of enzyme activity while ultrarapid (UM) and poor metabolizers (PM) have significantly increased or decreased levels of enzyme activity, respectively. 18 While the majority of the population are EMs, up to 7% of Caucasians are CYP2D6 PMs. 19 Some have concluded that desvenlafaxine may be preferred in this population since it does not require CYP2D6 for clinical activity or clearance unlike many other antidepressants including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, duloxetine, and venlafaxine. 11 , 13 , 16

In an attempt to quantify the effect of differences in metabolism between medications, the variances in medication metabolite plasma concentrations among CYP2D6 phenotypes have been measured. Studies evaluating plasma concentrations of venlafaxine and desvenlafaxine following administration of venlafaxine XR have clearly and consistently found the desvenlafaxine/venlafaxine ratio to be significantly lower in PMs when compared to EMs. 11 , 13 , 16 However, no difference in desvenlafaxine serum concentrations was found between PMs versus EMs following administration of desvenlafaxine in these studies. Of note, the sum of venlafaxine and desvenlafaxine did not differ between PM and EM groups receiving venlafaxine XR. 11 , 13 , 16 Considering that venlafaxine and desvenlafaxine are “pharmacologically approximately equiactive and equipotent” and clinical efficacy results from the net contribution of both compounds, one would not expect there to be clinically meaningful differences in efficacy and tolerability between PMs and EMs. 6

Studies have examined the possibility of decreased venlafaxine tolerability and efficacy in PMs versus EMs. One retrospective review that included patients who experienced adverse effects or insufficient clinical response to venlafaxine IR or XR found CYP2D6 PMs were significantly more likely to be on lower doses of venlafaxine (n=5100% taking 75 mg) versus other phenotypes (n=33 78.8% taking ≥150 mg). 14 Reasons for venlafaxine discontinuation or dose decrease in PMs included increased anxiety, insomnia, decreased appetite, somnolence, and fatigue. This finding may support the theory that CYP2D6 PM phenotype contributes to varied patient treatment response with venlafaxine however, demographics as well as initial dosing and dosing titrations were not consistent between groups. Prospective randomized trials are needed to confirm this conclusion. Another retrospective review included German patients who experienced adverse effects or insufficient clinical response while taking CYP2D6 dependent antidepressants (i.e., fluoxetine, n= 3 paroxetine, n=2 and fluvoxamine, n=1 amitriptyline, n=9 doxepin, n =5 venlafaxine, n=3 maprotiline, n=2 clomipramine, n=1 imipramine, n=1 trimipramine, n=1). 15 There was a significantly higher incidence of CYP2D6 PMs (28%) among those who experienced adverse effects or insufficient clinical response while taking CYP2D6 dependent antidepressants than found in the general population (7%). Unlike venlafaxine, other antidepressants included in this review do not have pharmacologically equivalent active metabolites. Therefore, increased side effects are expected to occur in CYP2D6 PMs as the parent drug serum concentration accumulates. Results of this review cannot be generalized to venlafaxine as statistical significance cannot be determined for the small number patients who experienced side effects on venlafaxine. Only one prospective study has demonstrated a statistically significant increased risk of side effects in PMs versus EMs taking a venlafaxine product. 12 When compared to EMs, CYP2D6 PMs taking venlafaxine IR for depression indications had a higher mean number of side effects (2.3 vs. 0.49 p<0.005) and lower mean serum sodium concentrations (138 vs. 142 mg/dL p<0.05). There does not appear to be a difference in severe side effects between the groups as the most commonly reported side effects were gastrointestinal side effects, and the difference in serum sodium concentrations does not appear to be clinically significant. 12 No significant differences in efficacy outcomes were found in these studies. 12 , 14–15 There is also one pooled analysis of four double blind, placebo-controlled trials (6 – 12 weeks) of patients with major depressive disorder that found significant differences in depression efficacy outcomes between EMs and PMs taking venlafaxine XR and IR. 11 The EMs had significantly greater improvements in change from baseline Hamilton Depression Rating Scale, 17-item (HAM-D17) and Montgomery Asperger Depression Rating Scale (MADRS) scores, HAM-D17 response rate, and MADRS response and remission rates. The HAM-D17 remission rates and incidence of side effects did not differ between the two groups. Despite the inherent limitations of this pooled analysis of clinical trials using varying venlafaxine formulations and protocols, these results suggest that CYP2D6 PMs may respond less favorably to venlafaxine XR therapy than EMs. 11 Head to head studies comparing efficacy of desvenlafaxine and venlafaxine XR in PMs are necessary to make definitive recommendations for treatment of this population. Because CYP2D6 PMs account for only 1 – 2% of African Americans 1% of Asians and up to 7% of Caucasians, it is not necessary to select desvenlafaxine over venlafaxine XR regularly to avoid intolerance or insufficient response to therapy. 19 Pharmacogenetic testing with the AmpliChip CYP450 may be helpful for some patients who experience intolerance or other difficulties with venlafaxine XR or other antidepressants. 19 Considering it costs approximately $2,000 yearly for desvenlafaxine and $150 yearly for generic venlafaxine XR (based on average wholesale price), it actually is less expensive to perform CYP2D6 phenotyping ($250 – $500) before initiating antidepressant therapy than to choose desvenlafaxine over venlafaxine for most patients. 19–20

Another potential difference between desvenlafaxine and venlafaxine XR is also related to metabolism: the risk for pharmacokinetic drug-drug interactions. Because desvenlafaxine has no significant effect on CYP2D6 at recommended doses, it is promoted as an appealing option to avoid potential drug-drug interactions with CYP2D6 substrates (e.g., many beta blockers, SSRIs, tricyclic antidepressants, opioids). However, venlafaxine XR is also unlikely to significantly affect CYP2D6 substrates. Venlafaxine IR was found to have lower inhibitory potency for CYP2D6 than any SSRI in in vitro studies. 22 Venlafaxine XR and desvenlafaxine have similar effects on substrates of CYP2D6 at recommended doses. In pharmacokinetic studies, venlafaxine IR 37.5 mg every 12 hours and desvenlafaxine 100 mg increased CYP2D6 substrate desipramine area under the curve (AUC) by 35% and 17% respectively. 2 , 6 It is interesting to note that a single dose of desvenlafaxine 400 mg increased desipramine AUC by 90%, so some CYP2D6 substrates with dose related side effects (e.g., tamoxifen, beta-blockers) may require dose reduction when combined with a higher dose of desvenlafaxine. 2 In regard to other potential mechanisms for interactions, both venlafaxine and desvenlafaxine are weak inhibitors of CYP3A4 and CYP1A2 and have minimal protein binding (27%, 30% respectively) making both agents unlikely to result in related interactions. 2 , 5 , 23 Combination with strong CYP2D6 inhibitors (i.e., paroxetine, fluoxetine, quinidine, bupropion) may impact venlafaxine XR more than desvenlafaxine, but clinical significance is unknown. 2 , 17 , 21 The combination of venlafaxine XR with a strong CYP2D6 inhibitor should result in decreased desvenlafaxine/venlafaxine ratios just as seen in patients who are CYP2D6 PMs. 6 Evidence of less favorable venlafaxine efficacy and tolerability with lower desvenlafaxine/venlafaxine ratios found in PMs is limited, and there does not appear to be a difference in serious adverse events when compared to EMs. 11–12 It is acceptable to combine venlafaxine XR with CYP2D6 inhibitors, if indicated. There are very few combinations that are likely to occur between venlafaxine XR and strong CYP2D6 inhibitors. SNRIs are not typically combined with SSRIs which leaves bupropion as the most likely interacting inhibitor.

The difference in FDA recommended dosing between venlafaxine XR and desvenlafaxine may make desvenlafaxine more appealing to some providers and patients. Desvenlafaxine is marketed as “an SNRI with a starting dose that is the proven effective dose” while venlafaxine XR requires titration to reach the maximum daily recommended dose of 225 mg. 6 , 17 However, comparison of bioavailability between venlafaxine XR and desvenlafaxine make this difference in recommended daily dosing somewhat unexpected. While the absolute bioavailability of venlafaxine XR is 45%, the bioavailability of total active drug is similar between venlafaxine XR (45% venlafaxine + 47% desvenlafaxine) and desvenlafaxine (80% desvenlafaxine). 2 , 6 This is illustrated in results from pharmacokinetic studies. Following administration of venlafaxine XR 75 mg to seven EMs, the mean (± SD) maximum plasma concentration (Cmax) and AUC were 30.1 ng/mL (17.7) and 518 (462) ng/mL for venlafaxine and 94.2 ng/mL (27.4) and 2589 (541) ng/mL for desvenlafaxine. When the same EMs were given desvenlafaxine 50 mg, the Cmax and AUC of desvenlafaxine were 84.5 ng/mL (15.4) and 2486 ng/mL (415), respectively. 13 Considering that the pharmacokinetics of venlafaxine XR and desvenlafaxine are linear and dose proportional up to 450 mg and 600 mg per day, respectively, one would expect equivalent doses of venlafaxine XR and desvenlafaxine to deliver similar amounts of total active drug (venlafaxine + desvenlafaxine) to systemic circulation. 2 , 6 Therefore, it may be unexpected to some that the FDA recommended daily target dose of desvenlafaxine is 50 mg since venlafaxine XR has demonstrated safety and efficacy up to 225 mg per day.

Clinical Trial Results

Despite pharmacokinetic similarities, clinical trial results are of primary importance when examining the safe and effective dosing range of desvenlafaxine. During development, Wyeth Pharmaceuticals sought approval for up to desvenlafaxine 200 mg daily, but the FDA selected 50 mg daily as the recommended dose. 10 Even though results from at least one of four 8-week double-blind, randomized, controlled clinical trials (Table 1) show statistically greater reductions in mean HAM-D17 total scores from baseline versus placebo for each desvenlafaxine dose studied (50 mg, 100 mg, 200 mg, 400 mg), the FDA rationalized that doses higher than 50 mg per day resulted in higher rates of side effects and discontinuations without any additional benefit. 17 , 24–27 Based on this rationale, it is unclear why the 100 mg tablet was also approved. Medications only need to achieve statistical separation from placebo in primary outcome (e.g., mean reduction of HAM-D17 score from baseline) to gain FDA-approval for the treatment of MDD, but depression response and remission rates should also be considered to judge a medication's clinically meaningful outcomes. Response and remission rates are inconsistent among doses in these four short-term trials, and it's possible that there are clinically meaningful differences between 50 mg and higher daily dosages.

Efficacy Results for 8-week, randomized, double blind, placebo controlled trials


Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors

To evaluate the possible influence of buspirone on sexual dysfunction in depressed patients treated with a selective serotonin reuptake inhibitor (SSRI), we analyzed data from a placebo-controlled trial designed to explore the efficacy of buspirone as add-on treatment for patients not responding to an SSRI alone. At baseline, all patients met the criteria for a major depressive episode according to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks without responding to the treatment. Buspirone (flexible dosage, 20-60 mg/day) or placebo was added to the SSRI for 4 weeks the mean daily dose of buspirone at endpoint was 48.5 mg (SD = 1.0). Sexual dysfunction was evaluated using a structured interview. Before starting medication with buspirone or placebo, 40% (47 of 117) reported at least one kind of sexual dysfunction (decreased libido, ejaculatory dysfunction, orgasmic dysfunction). During the 4 weeks of treatment, approximately 58% of subjects treated with buspirone reported an improvement with respect to sexual function in the placebo group, the response rate was 30%. The difference between placebo and active drug treatment was more pronounced in women than in men. The response was obvious during the first week, with no further improvement during the course of the study. It is suggested that the effect of buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual side effects rather than of an antidepressant effect of the drug.


Discussion

Patient education on the sexual side-effect profiles of SSRIs is critical to medication adherence, resolution of depressive symptoms, and improving quality of life. Delaying this discussion may result in confusion and distrust of pharmacotherapies and health care providers, making it more difficult to adjust and recommend medications later on. This literature review serves as an aid to better facilitate patient education and treatment. However, as with all narrative studies, flaws of this study include potential for selection bias as one reviewer was responsible for article selection. Additionally, given the wide breadth of articles analyzed, there may be some concerns with external validity because subject groups were heterogeneous. Lastly, antidepressants include a wide range of pharmacotherapy and nonpharmacotherapy options and not every facet was explored, potentially contributing to external bias.


Mental illness and sexual dysfunction

There is little in the literature specifically on older people's mental illness and sexuality however, the impact of mental illness on sexuality and sexual functioning is wide and well-studied. It has been estimated that only 44.9% of individuals with a severe mental illness were sexually active in the past 3 months, and perceptions of stigma and poor self-esteem are important mediators in the reduction of sexual activity (Bonfils Reference Bonfils, Firmin and Salyers 2015).

Depression and anxiety

Sexual dysfunction is strongly associated with depression and is related to several depressive symptoms, such as low energy, low motivation, poor self-esteem, anhedonia and reduced libido. As already discussed, this is compounded by many antidepressants conferring a risk of sexual side-effects. It has been suggested that the prevalence of sexual dysfunction in people with depression is twice that in healthy controls and that recurrent depression may be more associated with sexual dysfunction than single episodes of depression (Montejo Reference Montejo, Montejo and Baldwin 2018). A study that attempted to identify the baseline of sexual dysfunction in depressed individuals before treatment found that around one-third reported reduced interest in sex, with the most common dysfunction being reduced levels of arousal, followed by problems achieving orgasm or ejaculation (Thakurta Reference Thakurta, Singh and Bhattacharya 2012).

The burden of sexual dysfunction appears to be higher in major depressive illness (76%) than in the common anxiety disorders, although there are still significant rates of sexual dysfunction reported in conditions such as obsessive–compulsive disorder (OCD) (50%) and generalised anxiety disorder (64%), with low desire being the most common dysfunction (Kendurkar Reference Kendurkar and Kaur 2008). Fear of contamination during sexual activity is thought to be an important aspect of sexual dysfunction in OCD (Sabetnejad Reference Sabetnejad, Assarian and Omidi 2016). Reduced sexual functioning, however, can still be found in people with OCD irrespective of fears of contamination or medication use (Vulink Reference Vulink, Denys and Bus 2006).

A randomised controlled trial looked at response of sexual dysfunction in women with OCD to treatment with fluoxetine or cognitive–behavioural therapy (CBT) and found that those who received CBT showed significant improvement in areas of desire, arousal and orgasm though not in problems of reduced lubrication and dyspareunia (Sabetnejad Reference Sabetnejad, Assarian and Omidi 2016). There was a reported reduction in satisfaction and sexual function in the group treated with fluoxetine, possibly related to sexual side-effects (Sabetnejad Reference Sabetnejad, Assarian and Omidi 2016). The use of CBT more generally to target sexual dysfunction is an area where there is currently a lack of strong evidence to support formulation of guidelines (ter Kuile Reference ter Kuile, Both and van Lankveld 2010). Both OCD and panic disorders are seen to be related to sexual dysfunction independent of medication use therefore assessment of sexual functioning before psychotropic initiation could be an important aspect of treatment and prevention of further difficulties (Aksoy Reference Aksoy, Aksoy and Maner 2012).

Eating disorders

Sexual dysfunctions are commonly seen in eating disorders and the psychopathology of these disorders is thought to be an important factor in perpetuating these problems (Castellini Reference Castellini, Lo Sauro and Lelli 2013). The dysfunctions are likely to be multifactorial, including contribution from physiological changes related to low body weight and starvation (e.g. lethargy, amenorrhoea), comorbid depressive symptoms, problems with self-esteem and perceived body image (Castellini Reference Castellini, Lelli and Lo Sauro 2012). There is suggestion that the mechanisms of sexual dysfunction may vary between anorexia nervosa and bulimia nervosa: in one study, dysfunction was found to correlate with body mass index in anorexia, whereas the correlation found in bulimia was with depressive symptoms measured by the Beck Depression Inventory (Gonidakis Reference Gonidakis, Kravvariti and Varsou 2015).

Although treatment of sexual dysfunction in the eating disorder population has not been studied in detail it is thought that treatment focusing on body image, binge eating and emotional eating could improve sexual function (Castellini Reference Castellini, Lelli and Lo Sauro 2012). Psychotropic treatment of the eating disorder and any comorbid depressive illness would also appear to be a sensible approach to improving underlying dysfunctions, keeping in mind the difficulty with sexual side-effects.

Schizophrenia

Sexual dysfunction in schizophrenia is complex (Box 1): it can be related to symptoms of the condition (particularly negative symptoms), antipsychotic medication, comorbid physical health conditions, stigma and other psychosocial factors (de Boer Reference de Boer, Castelein and Wiersma 2015). A study of drug-free men with psychosis in India showed a prevalence of 25% for sexual dysfunction in those engaged in sexual activity dysfunction was related to both older age and later age at illness onset (Ravichandran Reference Ravichandran, Gopalakrishnan and Kuruvilla 2019). Other studies have suggested prevalence of dysfunction between 30 and 60% in drug-free patients with psychosis and prevalence as high as 80% in a more general population of men with schizophrenia (Ravichandran Reference Ravichandran, Gopalakrishnan and Kuruvilla 2019). In a rural Chinese population with schizophrenia 71.3% reported sexual dysfunction and this was associated again with old age and with burden of negative symptoms (Huang Reference Huang, Hou and Ng 2019). Although there is a paucity of research into this area it has also been suggested that loss of interest in sex in people with schizophrenia is associated with advancing age, female gender, cardiovascular medication, negative symptoms and lower sexual self-efficacy (self-confidence and self-control in sexual experiences) (Bianco Reference Bianco, Pratt and Ferron 2019). It is not clear whether treatment of the psychotic disorder confers an improvement in dysfunctions: a study of men with schizophrenia in remission still showed high levels of dysfunction (between 78.4 and 97.1%) across five domains of sexual functioning (Kheng Yee Reference Kheng Yee, Muhd Ramli and Che Ismail 2014). Another aspect of sexuality studied in schizophrenia is risky sexual behaviour, which refers to unprotected sex with risk of unwanted/unintended pregnancy and transmission of sexual diseases. A prevalence of 39.4% was reported in a study of 429 people with schizophrenia in Ethiopia, with associated factors including male gender, younger age, positive symptoms and substance misuse (Negash Reference Negash, Asmamewu and Alemu 2019).

BOX 1 Case vignette 1: antipsychotic treatment for sexualised behaviour in paranoid schizophrenia

A 78-year-old man with paranoid schizophrenia was admitted to hospital showing signs of mental disorder, including hallucinations, religious delusions, delusions of influence and paranoid delusions. He was displaying suspicious, hostile, aggressive and sexualised behaviour. He had falsely accused his daughter of incest, saying that she wanted to marry him. On the ward, he follows a female in-patient, wanting to tell her that he ‘does not have sperm anymore and wouldn't have children’. He tells doctors that he is concerned that he is not having erections, is sexually inactive and would like to be back to normal again. He has been masturbating every night but could not get any result.

A computed tomography (CT) head scan shows mild ischaemia and mild cerebral volume loss without lobar predominance. He scores 69/100 on the Addenbrooke's Cognitive Examination-III (ACE-III). There is no evidence of frontotemporal dementia.

With proper antipsychotic treatment his symptoms subsided and he was discharged from hospital back into the community.

Bipolar affective disorder

Bipolar affective disorder can be associated with both hyposexual disorders and hypersexuality, often related to the polarity of the current episode of the illness. Sexual dysfunction during bipolar depression can be thought of as similar to the dysfunction seen in a unipolar depressive illness, and as in that illness there are also reports of residual sexual dysfunction in euthymic patients (Montejo Reference Montejo, Montejo and Baldwin 2018). Residual sexual dysfunction has been shown to affect medication adherence in clinically stable individuals with bipolar disorder so is important to keep in mind when assessing the patient (Grover Reference Grover, Ghosh and Sarkar 2014). Sexual distress and dissatisfaction have been found to be higher in people with bipolar disorder than in the general population and higher rates of sexual desire are seen in these patients in comparison with those with unipolar depression (Sørensen Reference Sørensen, Giraldi and Vinberg 2017). Stigma again appears to play an important role in bipolar disorder: a US study found that rates of marriage were lower in adults with bipolar disorder (32.8%) than in the general population (55.7%), and 52.9% of patients felt that stigma affected their relationship success (Jackson Reference Jackson, Kolikonda and Yeruva 2018). Mania-induced hypersexuality and risky sexual behaviour is well-known but understudied in this population, as are lower intensity increases in sexual behaviour and the impact of cycling mood on relationships (Kopeykina Reference Kopeykina, Kim and Khatun 2016). Guidelines for treating acute manic episodes are well established but again there is little specific guidance on hypersexuality and the recurring problems of sexual side-effects of medication.


Why does venlafaxine have lower incidence of sexual dysfunctions at higher doses? - Psychology

SHELDON H. PRESKORN, MD

Journal of Practical Psychiatry and Behavioral Health, March 2000, 97-102

General Bucky Turgeson in the Stanley Kubrick movie, Dr. Strangelove, was mighty proud of his aerial warriors and their B-52s. This series of planes, first rolled out in the 1950s, are still being used. The longevity and value of these planes are the result of their ability to deliver so many different types of payloads to their targets.

For similar reasons, I suspect Bucky would have loved imipramine, mirtazapine, and nefazodone. These drugs are multiple action antidepressants that are capable of affecting multiple targets at the concentrations achieved over their clinically relevant dosing range (Figure 1). That fact distinguishes them from the norepinephrine selective reuptake inhibitors (NSRIs) (e.g., desipramine) and from the selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline) (Figure 2). NSRIs and SSRIs have a binding affinity for the site believed to mediate their antidepressant efficacy that is at least an order of magnitude greater than their binding affinity for other neural mechanisms of action. 5 In this column, I will focus on how the differences between the in vitro pharmacology of the multiple mechanism of action antidepressants (e.g., imipramine, mirtazapine, nefazodone) and that of the single mechanism of action antidepressants (i.e., SSRIs and NSRIs) account for the differences in their clinical pharmacology.

This column is the fifth in a series reviewing the clinical relevance of in vitro binding affinity. Although I have focused on antidepressants in this series, the basic pharmacological principles I have covered are applicable to any class of medications. The two primary principles underlying this series are:

  • In vitro binding affinity, while important, is only one factor in the equation that determines drug effect:
  • The drug level needed to engage the desired target to a physiologically meaningful degree dictates the dosing rate that is needed relative to the patient's ability to clear the drug. The relationship between drug level, drug dose, and drug clearance is expressed in the following equation:

In this column, I discuss how the data in Figure 1 relate to the clinical pharmacology of imipramine, mirtazapine, and nefazodone. In doing so, I present a pharmacological explanation for why both imipramine and mirtazapine have curvilinear dose-response curves with regard to some of their actions and why nefazodone has an ascending dose-antidepressant response curve like venlafaxine rather than the flat dose-antidepressant response curve seen with the SSRIs.

In the first column in this series, I made the point that a 10-fold separation in binding affinity between two targets is generally required to be able to achieve a drug concentration that will affect the highest affinity target to a physiologically meaningful degree without affecting the other target . 5 From this standpoint, imipramine is the antithesis of a selective drug. Within a concentration range that involves less than a 10-fold separation, imipramine binds to six targets: the uptake pumps for norepinephrine and serotonin and the histamine-1, muscarinic acetylcholine, serotonin 2A (5-hydroxy tryptamine-2A, 5-HT2A), and alpha-1 adrenergic receptors (Figure 1). Blockade of these receptors will cause sedation, dry mouth, and orthostatic hypotension, respectively, whereas inhibition of the uptake pumps is believed to mediate the antidepressant efficacy of these medications. 6

Figure 1 - Relative potency for different sites of action of non-SSRI antidepressants
- Based on data from Bolden-Watson C, Richelson E, 1993, Cusack B, et al. 1994 and
de Boer et al. 1988, 1995

Just as important, although not shown in Figure 1, imipramine also blocks the sodium fast channel at a concentration only slightly more than 10 times that needed to block the norepinephrine uptake pump. 6 That fact explains why the tertiary amine tricyclic antidepressants (TCAs) can cause cardiac conduction disturbances and why they have a narrow therapeutic index. The cardiotoxicity of these drugs results from their ability to inhibit fast sodium channels and thus prolong intracardiac conduction. 8 This prolongation in turn sets the stage for escape ventricular beats, which can result in a fatal ventricular arrhythmia. The 10-fold separation between imipramine's affinity for the norepinephrine uptake pump and for the fast sodium channels means that an imipramine concentration can be achieved that produces an antidepressant response without causing delayed intracardiac conduction. However, the fact that the separation is only slightly more than 10-fold means that taking an overdose consisting of the entire amount contained in a typical 2-week prescription can result in a fatal arrhythmia.

As I discussed in an earlier column, 7 these pharmacological properties are the reason tertiary amine TCAs such as imipramine served as the blueprint for the development of subsequent antidepressants. Studying the pharmacology of drugs like imipramine (Figure 1) and amitriptyline (Figure 2) helped us formulate hypotheses about what sites of action mediated their desired (e.g., antidepressant efficacy) and their undesired (e.g., dry mouth, cardiotoxicity) effects. These hypotheses in turn led to the synthesis of new drugs that mimic only part of the pharmacology of these older antidepressants.

Figure 2 - Relative potency for different sites of action of three different types of antidepressants.
- Based on data from Bolden-Watson C, Richelson E, 1993, Cusack B, et al. 1994

Curvilinear dose-response curves seem paradoxical to many people. They ask how a drug can produce an effect at one dose but not at a higher dose. The answer is that, at lower concentrations (i.e., low dose), the drug preferentially engages a site of action capable of mediating the first effect, but at higher concentrations (i.e., higher doses), the drug engages a second site of action that blocks or antagonizes the first effect. Imipramine has just such a curvilinear dose-response curve with regard to blood pressure. 9 At low concentrations, imipramine increases blood pressure by increasing the ionotrophic effect of norepinephrine on the myocardium and its vasoconstrictive effect on peripheral arterioles via its blockade of the norepinephrine uptake pump. Imipramine shares this action with other norepinephrine reuptake inhibitors, including its active metabolites, desipramine, and the serotonin-norepinephrine reuptake inhibitor, venlafaxine. 10 However, in contrast to desipramine and venlafaxine, imipramine at higher doses antagonizes its initial pressor effect on the cardiovascular system and can even cause orthostatic hypotension by blocking the alpha-1 adrenergic receptor resulting in decreased peripheral resistance. Since desipramine and venlafaxine do not block the alpha-1 adrenergic receptor over their clinically relevant dosing range, the likelihood and magnitude of their pressor effect simply increase as the dose of these drugs is increased.

As with all drugs, knowledge of the in vitro pharmacology of mirtazapine can help us understand its clinical pharmacology. Mirtazapine's most potent site of action is the histamine-1 receptor (Figure 1). At higher concentrations, the drug sequentially blocks the 5-HT2A receptor and then the alpha-2 adrenergic receptor (Figure 1). Although not illustrated in Figure 1, mirtazapine binds almost as avidly to the 5-HT2C and 5-HT3 receptors as it does to the 5-HT2A receptor. 3,4

Doses of mirtazapine needed to treat clinical depression result in concentrations sufficient to block the 5HT2A, 5-HT2C, 5-HT3, and the alpha-2 adrenergic receptors. Higher concentrations (and hence doses) are obviously needed to block the alpha-2 adrenergic receptor site than are needed to block the serotonin receptors. These facts are consistent with the hypothesis that one or more of these mechanisms mediate the antidepressant efficacy of mirtazapine. This constellation of mechanisms of action is not shared by any other antidepressant, which raises the possibility that mirtazapine might work in patients who have not benefited from other types of antidepressants. There is some evidence supporting this possibility. Two separate studies have indicated that mirtazapine can work in patients who have not benefited optimally from treatment with amtriptyline 11 or fluoxetine. 12

Based on its binding profile, some psychiatrists have used mirtazapine both to augment the antidepressant effects of serotonin uptake inhibitors (i.e., SSRIs and low dose venlafaxine) and to treat their adverse effects. To put this discussion in perspective, a few comments about the effects of SSRIs and venlafaxine may be helpful. These antidepressants are believed to work by increasing serotonin availability to the various serotonin receptors in the brain by slowing the neuronal reuptake of serotonin after its release. Thus, these drugs work as indirect serotonin receptor agonists. While SSRIs are "selective" in terms of directly affecting only the serotonin uptake pump, they are not "selective" in terms of their agonism of serotonin receptors. They increase serotonin availability to all serotonin receptors. Agonism of the 5-HT1A receptor is currently believed to be the mechanism mediating the antidepressant efficacy of these drugs. Conversely, agonism of the 5-HT2A, 5HT2C, and 5-HT3 receptors may principally mediate the adverse effects of these drugs: sleep disturbance, anxiety and weight gain, and nausea/loose stools/vomiting, respectively. 7

Mirtazapine at antidepressant concentrations blocks the 5-HT2A, 5-HT2C, and 5-HT3 receptors. Thus, the combination of this drug plus an SSRI or venlafaxine could simultaneously treat the adverse effects of these drugs while increasing the availability of serotonin to the 5-HT1A receptor, the putative mechanism mediating their antidepressant efficacy. Mirtazapine also blocks the alpha-2 adrenergic receptor (Figure 1). Thus, mirtazapine could act like yohimbine, another alpha-2 adrenergic antagonist, to treat sexual dysfunction caused by serotonin uptake inhibitors. However, that potentially desirable effect may be offset by its blockade of the histamine-1 receptor (you may simply be too tired to be frisky). Alpha-2 adrenergic antagonism also promotes the release of serotonin. That coupled with serotonin uptake inhibition could increase serotonin availability postsynaptically. That could either be beneficial (e.g., increased antidepressant efficacy) or adverse (e.g., serotonin syndrome) depending on the magnitude of the increase and at what postysynaptic receptors it occurs.

To address this issue, we conducted a study to determine what happens when patients who have been on the SSRI, fluoxetine, are immediately switched to mirtazapine. 12 Fluoxetine was used in this study for two reasons. First, it persists for weeks in the body even after abrupt discontinuation. For that reason, patients switched from fluoxetine to other drugs are actually being treated with both drugs for weeks after the switch, even though they and their physicians may not consider this fact when interpreting their response. Second, due to its inhibition of multiple cytochrome P450 enzymes, fluoxetine might interact both pharmacokinetically and pharmacodynamically with mirtazapine. 6

As expected, there was an interval of several weeks when these patients had measurable and pharmacologically relevant plasma concentrations of mirtazapine and fluoxetine plus norfluoxetine. None of the patients developed the serotonin syndrome and their adverse effects were qualitatively and quantitatively the same as those seen in patients on mirtazapine, 15 mg/day, alone. As also expected, fluoxetine did not appreciably alter the concentration of mirtazapine consistent with the fact that mirtazapine has multiple pathways for its elimination. 13

Mirtazapine, like imipramine, may have a curvilinear dose-response curve. There is some suggestion that sedation is more pronounced on low rather than high dose mirtazapine therapy (15 versus 30 mg/day or more). This suggestion is principally based on the fact that there was a higher incidence of sedation in the American trials, which used lower doses, than in the European trials, which used higher doses of mirtazapine. There may be other reasons for this finding but that discussion is beyond the scope of this paper. Suffice it to say that the multiple actions of mirtazapine suggest the following theoretical explanation for why this otherwise paradoxical observation might be true. The sedative effect of mirtazapine at low doses is consistent with its high affinity for the histamine-1 receptor. Given that mirtazapine binds more avidly to that site of action than to sites capable of mediating relief from a depressive episode (Figure 1), sedation occurs at doses of mirtazapine below those needed for antidepressant efficacy (i.e., less than 15 mg/day). However, higher doses of mirtazapine result in the blockade of the alpha-2 adrenergic receptor, which produces an alerting or arousal effect just like yohimbine and just the opposite of the sedation produced by the alpha-2 adrenergic agonist, clonidine. Thus, mirtazapine most likely causes sedation at low doses (i.e., concentrations) by preferentially blocking the histamine-1 receptor, while at higher doses (i.e., concentrations), mirtazapine blocks the alpha-2 adrenergic receptor, which theoretically could reduce its sedating effects to some degree. A fixed dose trial or another type of prospective study would be needed to rigorously test this concept.

The first target affected by nefazodone is the 5-HT2A receptor (Figure 1). As the concentration of nefazodone increases, it sequentially engages the alpha-1 adrenergic receptor and then the serotonin uptake pump (Figure 1). There is almost an order of magnitude difference between nefazodone's binding affinity for the 5-HT2A receptor and its affinity for the serotonin uptake pump. Moreover, nefazodone is converted into a triazolodione metabolite, which is over 100 times more potent as a 5-HT2A receptor blocker than an uptake pump inhibitor. 14 While this metabolite is ten times less potent than the parent drug as a 5-HT2A blocker, its trough concentrations under steady-state dosing conditions are ten times higher than that of the parent drug, consistent with its longer half-life (24 versus 4 hours). 15 Based on these facts, it should be possible to achieve concentrations of the parent drug nefazodone and its triazolo metabolite that cause substantial and sustained blockade of the 5-HT2A receptor without producing substantial and sustained inhibition of the serotonin uptake pump.

As with the SSRIs and venlafaxine, 16 human studies using platelets as a surrogate measure for central serotonin uptake inhibition have been done with nefazodone to examine its dose-dependent effects on this mechanism. Nefazodone at a dose of 300 mg/day for 14 days produces 20%-40% inhibition of serotonin uptake inhibition in comparison to the 70%-80% inhibition produced by the SSRIs and venlafaxine at their respective, lowest usually effective doses. 10,17-19

The degree of serotonin uptake inhibition produced by nefazodone, 300 mg/day, relative to the SSRIs and venlafaxine, is consistent with its in vitro binding affinity and its drug concentration. While nefazodone is capable of inhibiting the serotonin uptake pump, it is relatively weak in terms of its binding affinity. For example, nefazodone's binding affinity is three orders of magnitude weaker than paroxetine or sertraline. 20 Given that difference, some may find it surprising that nefazodone produces any inhibition of the serotonin uptake pump. It does so for the same reason that bupropion inhibits the dopamine uptake pump at its usually effective dose. 21 The reason is that the concentrations of nefazodone achieved within its clinically relevant dosing range are three orders of magnitude higher than the concentrations of the SSRIs (Table 1). 10

In fact, the low binding affinity of nefazodone for the serotonin uptake pump may partly explain why such relatively high concentrations of nefazodone are needed to achieve clinical efficacy as an antidepressant.

Parenthetically, the same point was made in the preceding column about concentrations of bupropion and its metabolites relative to their binding affinity for the dopamine and norepinephrine uptake pumps. 21 Nevertheless, the degree of serotonin uptake inhibition produced by nefazodone, 300 mg/day, is probably not sufficient in and of itself to produce an antidepressant response. The basis for this inference comes from fixed dose studies with citalopram, paroxetine, and venlafaxine, in which it was found that those antidepressants, at doses that should produce less than 70% inhibition of serotonin uptake inhibition, were not superior to placebo in the treatment of patients with major depression.10

Thus, the platelet uptake inhibition studies with nefazodone provide a heuristic explanation for several of the ways in which the clinical pharmacology of nefazodone differs from that of the SSRIs and venlafaxine.

First, at 300 mg/day, nefazodone does not appear to produce as robust an antidepressant response on average as do the lowest usually effective doses of SSRIs and venlafaxine. 15 This statement is based on the magnitude of the reduction of depressive severity as measured by the Hamilton Depression Rating Scale (HDRS) 25 score in the antidepressant group versus its parallel placebo control group in double-blind, efficacy trials.

Second, nefazodone, like venlafaxine and in contrast to the SSRIs, has an ascending dose-antidepressant response curve. 15 The difference is that, at its lowest recommended dose, venlafaxine produces a reduction in HDRS scores that is comparable to that seen with the SSRIs, whereas nefazodone, as already mentioned, does not. When the dose of nefazodone reaches the upper end of its recommended dose range, the reduction is comparable and perhaps even superior to the reduction produced by the SSRIs, but not as great as occurs with the highest dose of venlafaxine. 15

Third, low-dose nefazodone treatment causes a lower incidence of sexual dysfunction than occurs on sertraline and most likely the other SSRIs and venlafaxine. 26 As is often said, your strength is often also your weakness. Thus, the lower degree of serotonin uptake inhibition produced by low-dose nefazodone treatment relative to the SSRIs and venlafaxine could account for both its decreased antidepressant efficacy and its lower incidence of sexual dysfunction relative to these other antidepressants.

Several inferences can be drawn from these observations. First, the blockade of 5-HT2A receptors (i.e., the predominant action of nefazodone at 300 mg/day) is not as robust an antidepressant mechanism of action as is serotonin uptake inhibition. That inference is further supported by the fact that antidepressant clinical trials programs with more than one relatively pure 5-HT2A blocker have not shown superior efficacy over placebo. Second, the fact that nefazodone at higher doses is comparable and perhaps even superior to the SSRIs in terms of HDRS score reduction suggests that 5-HT2A blockade combined with serotonin uptake inhibition may be superior to either mechanism alone. That may either reflect a synergistic action, or it may be that 5-HT2A blockade reduces adverse effects due to serotonin uptake inhibition that either mimic depressive symptoms (e.g., insomnia) or lead to treatment discontinuation before efficacy is achieved. Conceivably, a drug with a smaller gap between its binding affinity for the 5-HT2A receptor versus the serotonin uptake pump might be more efficacious or better tolerated than either nefazodone or the SSRIs. Such inferences can lead to further discovery work to develop and test such a compound as an antidepressant. Third, these observations indicate why dose titration is more necessary with nefazodone than with most of the SSRIs to obtain an adequate antidepressant response. Unfortunately, the nonlinear pharmacokinetics of nefazodone make such dose titration more difficult than would be expected with a drug with linear pharmacokinetics. Further discussion of this topic is beyond the scope of this column.

Imipramine, mirtazapine, and nefazodone are at the opposite end of the spectrum from the SSRIs (e.g., sertraline) or the NSRIs (e.g., desipramine or reboxetine) in terms of number of mechanisms of action that are affected at concentrations achieved in the usual patient taking these drugs at their respective antidepressant doses. To the best of our knowledge, the behavioral pharmacology of the SSRIs and the NSRIs is constrained to the effects mediated by their single mechanism of action, serotonin uptake inhibition and norepinephrine uptake inhibition, respectively. In contrast, the pharmacology of imipramine, mirtazapine, and nefazodone is richer or more varied or more complicated (i.e., pick the spin you prefer) than that of the SSRIs as a result of their effects on multiple mechanisms of action. That pharmacology includes both desired and undesired effects, which are often mirror images of the same phenomenon. It is for this reason that drug therapy is rarely, if ever, foolproof and why proper education is needed to prescribe and monitor medications.

The goal of this series of columns has been to help clinicians better understand the differences in the in vitro pharmacology of the various antidepressants as they relate to their clinical pharmacology in patients. This knowledge may help clinicians optimize their selection of an antidepressant for a given patient by matching the pharmacology to the symptom profile of the patient. The clinician can also use this knowledge to help guide the choice of an alternative antidepressant if a patient either does not benefit from or does not tolerate treatment with the first antidepressant chosen.

In my next column, I will present tables that summarize the adverse effect profile of the antidepressants that have been reviewed in this series of columns. These tables will further demonstrate how our ability to predict the pharmacology of a drug depends on understanding the relationship between its pharmacodynamics and its pharmacokinetics.


Which Antidepressants Cause the Least Sexual Side Effects?

Sexual side effects and one&rsquos libido are an important issue when it comes to antidepressant medications and depression itself. All too often, this issue is ignored when antidepressants are prescribed by a family physician or general practitioner. Yet sexual side effects are important enough that they should be addressed.

Although the focus of most depression treatment is on the alleviation of symptoms commonly associated with depression, some people are more sensitive to sexual side effects than others in certain types of antidepressant medications. For some people, their sex life may also be just as important as alleviating the symptoms of depression.

Research on Sexual Side Effects and Antidepressants

A 2001 study out of the University of Virginia examining the prevalence of sexual dysfunction among antidepressant users reveals that while the drug classes known as selective serotonin reuptake inhibitors (SSRIs, such as Paxil or Zoloft) and serotonin and norepinephrine reuptake inhibitors (SNRIs, such as Effexor and Cymbalta) were associated with a higher rate of sexual dysfunction, other antidepressants were associated with significantly lower rates, namely bupropion (Wellbutrin) and nefazodone (Serzone). These data suggest that sexual dysfunction may be related to serotonergic antidepressant therapy.

Wellbutrin, the brand name of bupropion, had the lowest overall rate of sexual dysfunction. It was associated with a rate of 22% of the overall population. The sustained release formulation fared almost as well with a rate of 25%. In contrast, the SSRIs (Prozac, Paxil, Zoloft and Celexa), venlafaxine (Effexor) and mirtazapine (Remeron) averaged about 40%. When subjects were removed who had other probable causes of sexual dysfunction, the results were even better. Wellbutrin&rsquos rate dropped to 7% with the other medications dropping to between 23-30%.

Wellbutrin is a norepinephrine and dopamine reuptake inhibitor (NDRI). It is contraindicated in patients with a seizure disorder or those taking Zyban, which also contains bupropion. It is also contraindicated for those with a diagnosis of an eating disorder such as bulimia or anorexia and for those currently taking an MAOI.

Results were presented on May 8, 2001 at the American Psychiatric Association annual meeting.

What This Means

People who are sensitive to sexual side effects should ask their doctor about switching to an antidepressant such as Wellbutrin or Serzone, which have lower sexual side-effect profiles than other commonly prescribe antidepressants.


Four Newer Antidepressants: Should You Use Them?

Since 2011, 3 new antidepressants have been approved by the FDA, and another (ketamine) has been generating buzz as a potential off-label medication for depression. In this article, well take a step back and review the data on vilazodone (Viibryd), levomilnacipran (Fetzima), vortioxetine (Brintellix), and ketamine.

Vilazodone (Viibryd)

Vilazodone was approved by the FDA in January of 2011, making it the oldest of the newer antidepressants. Those who like tracking mechanisms of action are calling vilazodone a SPARI, which stands for serotonin partial agonist/reuptake inhibitor. The drug inhibits reuptake of serotonin (like SSRIs) and has partial agonism at 5-HT1A receptors (like buspirone). So, theoretically, giving your patients vilazodone is similar to giving them both an SSRI and buspironeat the same time. Is that a good thing? Nobody knows for sure. In the STAR*D trial, buspirone had a cameo appearance in one of the steps, being used as an augmenter of citalopram, and it worked as well as bupropion augmentationa finding that may or may not have any relevance to vilazodone.

When the drug was first approved, the word on the street was that it (1) may work faster than other antidepressants, (2) may have fewer sexual side effects, and (3) may be more effective for anxiety. We were skeptical of these claims then, as was the FDA (see TCPR, April 2011 and http://carlatpsychiatry.blogspot.com/2011/10/fda-slams-viibryd-better-sexual-profile.html). But new datahave accumulated since then. Well rely mainly on a review published in 2015, which included 4 later-stage and post-marketing studies, as opposed to the pre-approval studies that the FDA reviews (Hellerstein DJ et al, Core Evid 201510:4962).

Onset of action

The idea of faster onset of action was originally based on one piece of animal data and one piece of human data. The animal data showed that vilazodone quickly enhanced serotonin transmission in rats via 2 distinct mechanisms: 5-HT1A partial agonism and regular serotonin reuptake. In the human study, vilazodone showed statistically significant reduction in depression scores compared to placebo quite early, by week 1, although there was no active drug comparison (Rickels K et al, J Clin Psychiatry 200970(3):326333).

Two more recent studies showed greater improvement versus placebo as early as week 2 (Croft HA et al, J Clin Psychiatry 201475(11):e1291 e1298 Mathews M et al, Int Clin Psychopharmacol 201530(2):6774). However, antidepressant response at 2 weeks is not unique to vilazodone. Early improvement is the rule and not the exception for many antidepressants (Szegedi A et al, J Clin Psychiatry 200970(3):344353). In addition, when researchers focused on remission instead of response, vilazodone took 6 full weeks to outperform placebo. The bottom line is that there is no convincing evidence that vilazodone has a faster onset of action than any of its competitors.

Sexual side effects

Early studies suggesting a cleaner sexual side effect profile for vilazodone were problematic. First, there was no SSRI comparator, which would have been necessary to make any claims that vilazodone had an advantage over other agents. Second, most of the patients enrolled had preexisting sexual dysfunction before being randomized to vilazodone or placebo. One can argue that this design has the advantage of being generalizable to many of our patients, who have underlying sexual dysfunction due to depression or age, for example. On the other hand, its akin to testing whether a drug has a headache side effect by giving it to a bunch of people who already had headaches. Any new onset headaches would be obscured by the pathology already there. And indeed, in the company-funded study, treatment with vilazodone didnt worsen the already high burden of sexual side effectsin fact, it was no different from placebo, both of which resulted in a slight improvement in sexual functioning (Rickels K et al, J Clin Psychiatry 200970(3):326333).

In a more recent industry-funded post-hoc analysis of patients with normal baseline sexual function who were randomized to vilazodone, citalopram, or placebo, there were no significant differences in onset of new sexual side effects. The rates were: placebo: 12% vilazodone 20 mg/day: 16% vilazodone 40 mg/day: 15% and citalopram 40 mg/ day: 17% (Mathews MG et al, Abstract 45, ASCP 2014 http://ascpmeeting.org/wp-content/uploads/2014/06/Poster-Session-Book-Final-6-29.pdf). There was also no significant difference among those who had baseline sexual dysfunction: 33% of patients on placebo, 35% on vilazodone 20 mg/day, 30% on vilazodone 40 mg/ day, and 28% on citalopram patients improved to normal sexual function by the end of the study.

According to the website ClinicalTrials.gov, there are ongoing studies of vilazodone addressing the sexual function issue. Until those results are published, we continue to consider the low sexual side effect claims as unsubstantiated.

Efficacy in anxiety

Theres a theoretical argument to be made that vilazodones 5-HT1A partial agonism might give it special anti-anxiety power. The only clinical trial evidence thus far is based on comparisons with placebo. As is true for many other antidepressants, vilazodone reduces scores on the Hamilton Anxiety Rating Scale more than placebo (Rickels K et al, J Clin Psychiatry 200970(3):326 333 Khan A et al, J Clin Psychiatr 201172(4):441447). Another analysis of these data found that vilazodone may be more effective for the subgroup of anxious depressed patients than for the non-anxious depressed (Thase ME et al, Int Clin Psychopharmacol 201429(6):351356). Promising, but wed need data comparing this medication with other antidepressants to be convinced that it has an advantage.

TCPR Verdict: Based on this second look at vilazodone, we dont see any new evidence that it works faster, has fewer sexual side effects, or is preferred in depressed patients with significant anxiety. We consider this a second-line antidepressant to be used after generics have failed.

Levomilnacipran (Fetzima)

Levomilnacipran was approved by the FDA in July 2013 for major depressive disorder. It is the close chemical cousin (an enantiomer) of milnacipran (Savella), approved in the U.S. in 2009 for fibromyalgia and approved for depression in other countries. Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI), which puts it in the same class as duloxetine (Cymbalta), venlafaxine (Effexor XR), and desvenlafaxine (Pristiq). However, levomilnacipran is more selective for inhibiting norepinephrine reuptake than the othersstudies have shown that it has a 15-fold higher selectivity for norepinephrine than for serotonin. This selectivity disappears at higher doses.

But does norepinephrine selectivity mean anything clinically? Some researchers have hypothesized that there is a norepinephrine deficit depression, associated with poor concentration, inattention, low motivation, lack of energy, and cognitive impairment. This might be distinct from a serotonin deficit depression, more associated with anxiety, appetite disturbances, and suicidality (Moret C et al, Neuropsychiatr Dis Treat 20117Suppl1:913 Nutt DJ, J Clin Psychiatry 200869SupplE1:47). It would be nice if we could someday identify depressive subtypes that respond to specific medications, but the evidence for this norepinephrine/ serotonin division is still indirect and preliminary.

Nonetheless, these speculations provide promotional talking points for reps, who may argue that their drug has a special norepinephrine-based power to improve impaired daily functioning. Lets look at the data.

Evidence on improving functioning

According to a recent meta-analysis, 4 out of 5 double-blind, placebo-controlled, short-term studies found that levomilnacipran was more effective than placebo for overall depressive symptoms (Montgomery SA et al, CNS Spectr 20145:19). The average response rate was 46% for levomilnacipran (vs. 36% on placebo) and the average remission rate was 28% (vs. 22% on placebo).

These studies also assessed change in functionality as a secondary measure. This was done using the Sheehan Disability Scale (SDS), a self-rating scale which asks about work/school, social life, and family life to measure functionality. Each of the three domains is scored from 0 (unimpaired) to 10 (extremely impaired). Any domain with a score of 5 or higher means significant functional impairment. So an SDS score of <12 total and <4 on all subscales indicates functional responders. An SDS score of <6 total and <2 on all subscales means functional remitters.

The meta-analysis reported a mean change in SDS score that was significantly greater with levomilnacipran compared to placebo but the actual difference in score was small, only a mean of 2.2 points better than placebo, (Sambunaris A et al, Int Clin Psychopharmacol 201429(4):197205). The pooled response ratethat is, the percent of patients who functioned better at the end of the trialwas 39% for levomilnacipran vs. 29% on placebo, and the pooled remission rate was 22% vs. 15% on placebo.

Of course, the skeptic in us points out that any medication that eases depression is likely to also improve functioning. It may be that all antidepressants, regardless of their mechanisms of action, are just as effective as levomilnacipran for impaired functioning. Unfortunately, the company has not compared its drug with anything more robust than placebo, so we dont know the answer yet.

An interesting secondary, post-hoc analysis of 1 of the 10-week placebo-controlled levomilnacipran studies looked at individual items in the major depression scales. The results didnt support that levomilnacipran was better at any particular neurotransmitter profile of symptoms. Instead, the drug improved the same types of symptoms targeted by other antidepressants. So its unclear whether the higher selectivity for norepinephrine truly relates with any significant clinical outcome (Montgomery SA et al, Int Clin Psychopharmacol 201429(1):2635).

TCPR Verdict: Levomilnacipran is an SNRI with especially strong reuptake inhibition of norepinephrine as opposed to serotonin. But whether it has any clear efficacy advantages over its competitors is not clear.

Vortioxetine (Brintellix)

Vortioxetine was approved by the FDA in September of 2013 for major depression. Its considered a multimodal agent, meaning that it acts not only as a serotonin reuptake inhibitor but also affects several other serotonin receptors. It is an agonist of 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3 and 5-HT7 receptors.

How well does vortioxetine work? A recent review of published and unpublished trials of the medication found 14 short-term randomized trials (6 to 12 weeks) eight of which were positive, five were negative, and one was considered failed because neither vortioxetine nor the active control, duloxetine, showed symptomatic improvement over placebo (Kelliny M et al, Ther Clin Risk Management 201511:11921212). Some studies compared vortioxetine to placebo, others to duloxetine or venlafaxine. Vortioxetine showed no clear superiority over active controls in measures of response or remission. So while vortioxetine has a distinctive pharmacological profile (Citrome L, Int J Clin Pract 201468(1):6082), it is no more effective for core depressive symptoms than standard antidepressants.

The approved dose of vortioxetine is 1020 mg/day. Sexual dysfunction has been reported to be minimal, but most premarketing trials relied solely on spontaneous reporting of adverse effects, which is known to underestimate their frequency (Cosgrove L et al, Account Res 2016 [Epub ahead of print]), and in one of the few trials that used a scale to measure effects on sexual performance, the authors concluded that the sample number is too small to draw any conclusions (Mahableshwarkar AR et al, J Clin Psychiatry 201576(5):583591).

Is vortioxetine a smart pill?

As we know, diminished ability to think or concentrate is one of the DSM-5 criteria for major depression. Specific domains such as executive function, processing speed, attention, and learning and memory, have been found to be deficient during acute major depressive disorder (MDD) (Hammar A and Ardal G, Front Hum Neurosci 20093:26).

In an effort to get a leg up on its competitors, the manufacturer has done studies showing that vortioxetine improves patients performance on experimental cognitive tasks. Preclinical trials found that subjects on vortioxetine did better than those on duloxetine on the Digit Symbol Substitution Task (DSST), a measure of psychomotor speed (Gonzalez-Blanch C et al, Arch Clin Neuropsychol 201126(1):4858). They then used the same outcome in 2 larger studies, each with 602 subjects. After 8 weeks, subjects on vortioxetine had higher scores on the DSST compared to those on placebo or those taking duloxetine, but by only 1.5%3.0% (2 to 4 points on a 133-point scale) compared to placebo, and <0.5% (0.5 points) compared to duloxetine. On the strength of these studies, the company is applying for a new cognitive dysfunction in MDD indication. An FDA expert advisory panel recommended the approval in February, but just as we were sending this issue to press, the agency announced it would deny an expanded indication for cognitive dysfunction (http://www.biopharmadive.com/news/in-reversalfda-denies-cognitive-dysfunction-labelexpansion-for-brintelli/416536/).

We assume that the FDAs skepticism was related to a couple of important questions: First, do improvements on the DSST score translate into functional improvements that we (or our patients) would recognize clinically? Second, is vortioxetine any better than other antidepressants for improving cognition in depression?

In terms of the meaningfulness of its pro-cognitive properties, a recent meta-analysis found that while vortioxetine improves performance in the DSST, it didnt help patients on 3 other cognitive tests. These include the Stroop test (a measure of cognitive control), the TrailMaking Test B (executive function), and the Rey Auditory Verbal Learning Test (delayed recall) (Rosenblat JD et al, Int J Neuropsychopharmacol 201519(2).pii: pyv082.doi:10.1093/ijnp/pyv082). As a smart pill, vortioxetines effects seem limited to one specific testwhich doesnt improve our confidence in its efficacy.

Finally, are the cognitive benefits of vortioxetinehowever modest they may bea direct pro-cognitive effect? Or do they indirectly follow from vortioxetines role as an antidepressant, thus implying that it wont perform better than any other treatment that eases depression? This question has not yet been fully answered, although one manufacturer-sponsored trial claims that the higher DSST scores were independent of its antidepressant effect (Mahableshwarkar AR et al, Neuropsychopharm 201540(8):20252037). Similar claims have also been made for duloxetine (Greer TL et al, Dep Res Treat 2014. Published online 2014 Jan 19. doi: 10.1155/2014/627863), but other antidepressants simply havent been studied for their cognitive benefits.

TCPR Verdict: Will Brintellix make your patients Brintellectuals? The FDA is skeptical, and so are we.

Ketamine is not FDA approved for depression, but rather for preoperative general anesthesia. And it doesnt act on serotonin, norepinephrine, or dopamine instead, its an antagonist of the NMDA subtype of the glutamate receptor. It has long had illicit popularity in the party and rave scene under the nickname special K. Of relevance to psychiatrists, ketamine has been touted as a potential fast-acting miracle antidepressant, and many clinicians are already offering it off-label to their patients in pop-up ketamine clinics. Should you jump on the ketamine bandwagon?

The ketamine antidepressant data

As of late 2015, nearly a dozen randomized clinical trials of intravenous ketamine for the treatment of depression had been published (DeWilde KE et al, Ann NY Acad Sci 20151345:4758). These include some placebo-controlled trials, in addition to some open-label trials and a few trials with an active control (usually midazolam [Versed]). All showed, on average, a statistically significant responsedefined as a 50% reduction in MADRS or Hamilton Rating Scale for Depression (HAM-D) symptomscoreswithin 24 hours. Response rates have ranged from 40% to 70%. Some studies used only a single dose, with an antidepressant effect lasting up to 72 hours (even longer in some studies), while others involved repeated IV administrations over 2 weeks. The typical ketamine dose was 0.5 mg/kg given over a 40-minute periodas opposed to the anesthetic dose, which ranges from 1.04.5 mg/kg IV usually given over one minute.

Other studies have found that single infusions reduce suicidal ideation at 4 and 24 hours post-infusion (Price RB et al, Biol Psychiatry 200966:522526). Investigators are now trying to identify subgroups who are more likely to respond to ketamine. There arent enough data yet to predict response, but some potential positive indicators include a family history of alcoholism, comorbid anxiety, or an elevated body mass index (Niciu MJ et al, J Clin Psychiatry 201475:e417423).

Ketamine in the office?

So if it provides such rapid relief to some people who have been refractory to other treatments, why hasnt ketamine caught on? One major hurdle, of course, is the fact that its an intravenous medication, making it much more complicated to prescribe than a pill. Because of potential, though rare, side effects such as an acute hypertensive crisis, the IV infusion should take place in a medical office equipped with vital sign monitoring, airway equipment, oxygen, and a crash cart. Some even advise the presence of a trained anesthesiologist (Sisti D et al, Curr Psychiatry Rep 201416:527). These requirements likely explain the high outof-pocket costs (up to $500$750 per infusion) for this off-label procedure at the handful of ketamine clinics that have popped up nationwide over the last few years. Other potential adverse effects, like an uncomfortable dissociative experience, as well as long-term cognitive impairment and the risk of diversion or recreational abuse of ketamine, must be considered.

Furthermore, no one really knows how long to provide the treatment. In the 2-week trials described above, which involved 6 infusions, relapse rates were as high as 55% to 89% in the month following treatment (Newport DJ et al, Am J Psychiatry 2015172:950966). No maintenance strategy has been described, and no other medications have been shown to extend ketamines antidepressant effect.

Finally, its still not clear that the standard 0.5 mg/kg intravenous dose is the best dose. This dose was chosen, in part, because it produces few side effects these are typically transient dissociative symptoms (I feel like Im floating) or hallucinations during the infusion. While these effects are short-lived, they have also been positively associated with a treatment response (Luckenbaugh DA et al, J Affect Disord 2014159:5661). Thus, dissociative effects may predictor may even be responsible forthe antidepressant effect. If this is true, it may be hard to find a dose that minimizes unpleasant psychoactive effects while also producing a robust antidepressant effect. Then again, some practitioners are deliberately using higher doses of ketamine,sometimes in intramuscular or oral forms, in order to induce a psychedelic state, which they see as a necessary component of healing (Dakwar E et al, Drug Alc Depend 2014136:153157).

Pharmaceutical companies have eagerly embraced the ketamine story, in hopes of developing a similar drug without ketamines reputation and its pesky DEA Schedule III designation. But the options are limited. AstraZeneca tested one compound, lanicemine, but quietly backed out after it failed a Phase IIb trial in 2015. Another compound called GLYX-13 (recently renamed rapastinel), a partial agonist at another site on the NMDA receptor, has been effective in reducing HAM-D scores relative to placebo at some doses, and further research is ongoing. Other labs are studying the tuberculosis drug Dcycloserine, another NMDA modulator, as well as other agents. The closest thing to ketamine in the commercial pipeline is Janssens intranasal S-ketamine (an enantiomer of ketamine), currently in phase II trials.

Of course, if you want to explore this territory on your own, IV ketamine is readily available. It can be compounded into oral, sublingual, and intranasal forms. But its use in depression remains strictly off-label and, at this time, must be seen as experimental. As more data become available and protocols are published and refined, it may be worth your time and effort to add it to your repertoire.

TCPR Verdict: Ketamine looks promising for extremely rapid relief of depressionbut the effects are short-lived, and any antidepressant that requires a crash cart nearby is not likely to become a blockbuster.


What are the sexual side effects of antidepressants?

For many, taking antidepressants means experiencing some form of sexual dysfunction.

Experts are still researching the sexual side effects caused by antidepressants to figure out why they happen and how to prevent them. There may be some antidepressants that cause fewer sexual side effects, and there are also promising ways to manage or prevent these effects.

Share on Pinterest The sexual side effects from taking antidepressants will vary from person to person and will be different for men and women.

Taking antidepressant drugs can cause a wide range of side effects. Everything from gut issues to anxiety have been reported by people who take antidepressants.

Until recently, the sexual side effects caused by antidepressants were not often discussed with patients before prescribing the medications.

The symptoms of sexual dysfunction caused by taking antidepressants were highlighted in a recent study posted to Drug, Healthcare and Patient Safety.

Commonly reported symptoms include:

  • decreased sexual desire
  • loss of sexual excitement
  • diminished or delayed orgasm
  • loss of sensation
  • persistent genital arousal

These symptoms can change from person to person. There are also some symptoms that are particular to men and women. In men, more specific symptoms may occur, such as trouble getting or keeping an erection, or a persistent and painful erection. Men may also experience delayed or painful ejaculation.

Specific symptoms of sexual dysfunction caused by antidepressants in women include lactation that is not due to pregnancy or breastfeeding, and numbness in the vagina and nipples.

The symptoms of sexual dysfunction can impact a person’s quality of life. This can affect relationships, decrease self-esteem, and lead some people to stop taking their medication in order to find relief from the symptoms.

However, stopping taking medication abruptly can lead to withdrawal symptoms so this is not recommended. People who are experiencing sexual side effects could try some management techniques instead.

The reason that antidepressants cause sexual side effects is not fully understood. Depression itself can cause sexual side effects as well, so it can be difficult to understand which symptoms are caused by the disorder and which are caused by the medicine.

The side effects may also be due to the fact that each drug acts in a slightly different way in the body. For instance, selective serotonin reuptake inhibitors (SSRIs) work to increase the amount of serotonin circulating in the brain.

Serotonin helps the user feel less depressed and anxious, but too much serotonin may inhibit a person’s sex drive and make it harder to experience sexual pleasure.

Another theory is that as serotonin is increased, the levels of dopamine are decreased. This would be significant because dopamine is a chemical in the body that people need to feel stimulated. With less dopamine in the body, a person may have a hard time feeling sexually aroused.

Each antidepressant medication acts differently in the body. All of the main types of antidepressant have been linked to sexual side effects. The prevalence varies by the study and specific medication, however.

SSRIs

While there are many people who have sexual dysfunctions when taking all types of antidepressants, it is most commonly reported with SSRIs. Brand names include Zoloft, Prozac, and Paxil, among others.

A report in Drug, Healthcare and Patient Safety indicates that 58 to 70 percent of people who take SSRIs experience sexual side effects.

Tricyclic antidepressants (TCAs)

TCAs such as amitriptyline may be a better option for many patients. Amitriptyline was linked to sexual side effects in an estimated 7.7 to 10 percent of depressed people.

It seems that TCAs are a much better option than SSRIs for people with sexual dysfunctions caused by antidepressant drugs.

5-HT2 blockers

According to the report in Drug, Healthcare and Patient Safety, people who took newer 5-HT2 blockers experienced less symptoms of sexual dysfunction than those who took SSRIs.

For example, 8 percent of people taking the drug nefazodone experienced sexual side effects, while the drug mirtazapine produced sexual side effects in 24 percent of its cases. These figures are quite a lot lower than those reported with SSRIs.

People who are interested in switching medications should talk to their doctors for full details.

Monoamine oxidase inhibitors (MAOIs)

According to a journal posted in South African Family Practice, certain MAOIs have been associated with sexual side effects. This number does depend on the type of MAOI itself.

For instance, the drug phenelzine was associated with sexual dysfunction in up to 40 percent of cases.

Reversible inhibitor or monoamine oxidase A (RIMA)

When looking to avoid sexual side effects while taking antidepressants, many users turn to the RIMA drug moclobemide. Its brand names include Aurorix, Amira, and others.

Moclobemide appears to have a much lower incidence of sexual side effects. Less than 4 percent of moclobemide users reported sexual side effects while taking the drug. The drug is common in Australia and Finland, but is not approved for use in the United States.

Sexual dysfunction does not have to be a permanent side effect of taking antidepressants. In some cases, patients experience these symptoms within the first few weeks or months of taking their prescription, and then the symptoms become less severe.

Many people on antidepressants may also find success through managing their sexual side effects in one or more ways.

Switching medication

If the side effects caused by antidepressants are severe or very persistent, it may be possible to switch medications to try out results on another medication.

Working with their doctor, an individual will gradually come off their current medication and move to a new one. After a suitable trial period, the doctor may evaluate the person to see whether to change the dosage of the medication.

Lowering dosage

The dosage of the medication may also have an effect on the sexual side effects the patient experiences. If a patient feels their dosage is too high, they can have it evaluated by their doctor.

The doctor will begin putting the patient on lower doses of the drug. They will then monitor their progress to determine the lowest dose of the drug the person can take for it to be effective. Dosage is a very individual thing, and should not be adjusted without guidance from a doctor.

Personal changes

There are also ways to raise the libido without adjusting medications.

For many people, it is the will to have sex that is most affected by antidepressant medications. They may be physically able to be aroused, yet lack the willpower to carry out the act.

In these cases, it may be helpful to allow the body to go through the motions that usually make the person feel sexually aroused. Engaging in foreplay can stimulate the body and may help to influence the mind and increase the libido naturally.

Doctors may also recommend that people who take their medication on a daily basis, engage in sexual activity before taking their medication. In some cases, adding a sexual stimulant drug may help improve sex drive. As always, people should discuss these options with a doctor.

Because antidepressants may also decrease the amount of dopamine in the body, it is important for people taking them to boost their natural levels of dopamine. This can be as simple as getting plenty of rest and exercise, while also reducing stress levels.

Outlook

Many of the antidepressants on the market are linked to sexual side effects. The symptoms vary from person to person, but can greatly affect an individual’s life.

Managing these side effects can require a mixture of lifestyle changes, different medication, and dosage corrections. Working directly with a doctor, patients can help to reduce or eliminate sexual side effects caused by antidepressants.


Why does venlafaxine have lower incidence of sexual dysfunctions at higher doses? - Psychology

SHELDON H. PRESKORN, MD

Journal of Practical Psychiatry and Behavioral Health, March 2000, 97-102

General Bucky Turgeson in the Stanley Kubrick movie, Dr. Strangelove, was mighty proud of his aerial warriors and their B-52s. This series of planes, first rolled out in the 1950s, are still being used. The longevity and value of these planes are the result of their ability to deliver so many different types of payloads to their targets.

For similar reasons, I suspect Bucky would have loved imipramine, mirtazapine, and nefazodone. These drugs are multiple action antidepressants that are capable of affecting multiple targets at the concentrations achieved over their clinically relevant dosing range (Figure 1). That fact distinguishes them from the norepinephrine selective reuptake inhibitors (NSRIs) (e.g., desipramine) and from the selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline) (Figure 2). NSRIs and SSRIs have a binding affinity for the site believed to mediate their antidepressant efficacy that is at least an order of magnitude greater than their binding affinity for other neural mechanisms of action. 5 In this column, I will focus on how the differences between the in vitro pharmacology of the multiple mechanism of action antidepressants (e.g., imipramine, mirtazapine, nefazodone) and that of the single mechanism of action antidepressants (i.e., SSRIs and NSRIs) account for the differences in their clinical pharmacology.

This column is the fifth in a series reviewing the clinical relevance of in vitro binding affinity. Although I have focused on antidepressants in this series, the basic pharmacological principles I have covered are applicable to any class of medications. The two primary principles underlying this series are:

  • In vitro binding affinity, while important, is only one factor in the equation that determines drug effect:
  • The drug level needed to engage the desired target to a physiologically meaningful degree dictates the dosing rate that is needed relative to the patient's ability to clear the drug. The relationship between drug level, drug dose, and drug clearance is expressed in the following equation:

In this column, I discuss how the data in Figure 1 relate to the clinical pharmacology of imipramine, mirtazapine, and nefazodone. In doing so, I present a pharmacological explanation for why both imipramine and mirtazapine have curvilinear dose-response curves with regard to some of their actions and why nefazodone has an ascending dose-antidepressant response curve like venlafaxine rather than the flat dose-antidepressant response curve seen with the SSRIs.

In the first column in this series, I made the point that a 10-fold separation in binding affinity between two targets is generally required to be able to achieve a drug concentration that will affect the highest affinity target to a physiologically meaningful degree without affecting the other target . 5 From this standpoint, imipramine is the antithesis of a selective drug. Within a concentration range that involves less than a 10-fold separation, imipramine binds to six targets: the uptake pumps for norepinephrine and serotonin and the histamine-1, muscarinic acetylcholine, serotonin 2A (5-hydroxy tryptamine-2A, 5-HT2A), and alpha-1 adrenergic receptors (Figure 1). Blockade of these receptors will cause sedation, dry mouth, and orthostatic hypotension, respectively, whereas inhibition of the uptake pumps is believed to mediate the antidepressant efficacy of these medications. 6

Figure 1 - Relative potency for different sites of action of non-SSRI antidepressants
- Based on data from Bolden-Watson C, Richelson E, 1993, Cusack B, et al. 1994 and
de Boer et al. 1988, 1995

Just as important, although not shown in Figure 1, imipramine also blocks the sodium fast channel at a concentration only slightly more than 10 times that needed to block the norepinephrine uptake pump. 6 That fact explains why the tertiary amine tricyclic antidepressants (TCAs) can cause cardiac conduction disturbances and why they have a narrow therapeutic index. The cardiotoxicity of these drugs results from their ability to inhibit fast sodium channels and thus prolong intracardiac conduction. 8 This prolongation in turn sets the stage for escape ventricular beats, which can result in a fatal ventricular arrhythmia. The 10-fold separation between imipramine's affinity for the norepinephrine uptake pump and for the fast sodium channels means that an imipramine concentration can be achieved that produces an antidepressant response without causing delayed intracardiac conduction. However, the fact that the separation is only slightly more than 10-fold means that taking an overdose consisting of the entire amount contained in a typical 2-week prescription can result in a fatal arrhythmia.

As I discussed in an earlier column, 7 these pharmacological properties are the reason tertiary amine TCAs such as imipramine served as the blueprint for the development of subsequent antidepressants. Studying the pharmacology of drugs like imipramine (Figure 1) and amitriptyline (Figure 2) helped us formulate hypotheses about what sites of action mediated their desired (e.g., antidepressant efficacy) and their undesired (e.g., dry mouth, cardiotoxicity) effects. These hypotheses in turn led to the synthesis of new drugs that mimic only part of the pharmacology of these older antidepressants.

Figure 2 - Relative potency for different sites of action of three different types of antidepressants.
- Based on data from Bolden-Watson C, Richelson E, 1993, Cusack B, et al. 1994

Curvilinear dose-response curves seem paradoxical to many people. They ask how a drug can produce an effect at one dose but not at a higher dose. The answer is that, at lower concentrations (i.e., low dose), the drug preferentially engages a site of action capable of mediating the first effect, but at higher concentrations (i.e., higher doses), the drug engages a second site of action that blocks or antagonizes the first effect. Imipramine has just such a curvilinear dose-response curve with regard to blood pressure. 9 At low concentrations, imipramine increases blood pressure by increasing the ionotrophic effect of norepinephrine on the myocardium and its vasoconstrictive effect on peripheral arterioles via its blockade of the norepinephrine uptake pump. Imipramine shares this action with other norepinephrine reuptake inhibitors, including its active metabolites, desipramine, and the serotonin-norepinephrine reuptake inhibitor, venlafaxine. 10 However, in contrast to desipramine and venlafaxine, imipramine at higher doses antagonizes its initial pressor effect on the cardiovascular system and can even cause orthostatic hypotension by blocking the alpha-1 adrenergic receptor resulting in decreased peripheral resistance. Since desipramine and venlafaxine do not block the alpha-1 adrenergic receptor over their clinically relevant dosing range, the likelihood and magnitude of their pressor effect simply increase as the dose of these drugs is increased.

As with all drugs, knowledge of the in vitro pharmacology of mirtazapine can help us understand its clinical pharmacology. Mirtazapine's most potent site of action is the histamine-1 receptor (Figure 1). At higher concentrations, the drug sequentially blocks the 5-HT2A receptor and then the alpha-2 adrenergic receptor (Figure 1). Although not illustrated in Figure 1, mirtazapine binds almost as avidly to the 5-HT2C and 5-HT3 receptors as it does to the 5-HT2A receptor. 3,4

Doses of mirtazapine needed to treat clinical depression result in concentrations sufficient to block the 5HT2A, 5-HT2C, 5-HT3, and the alpha-2 adrenergic receptors. Higher concentrations (and hence doses) are obviously needed to block the alpha-2 adrenergic receptor site than are needed to block the serotonin receptors. These facts are consistent with the hypothesis that one or more of these mechanisms mediate the antidepressant efficacy of mirtazapine. This constellation of mechanisms of action is not shared by any other antidepressant, which raises the possibility that mirtazapine might work in patients who have not benefited from other types of antidepressants. There is some evidence supporting this possibility. Two separate studies have indicated that mirtazapine can work in patients who have not benefited optimally from treatment with amtriptyline 11 or fluoxetine. 12

Based on its binding profile, some psychiatrists have used mirtazapine both to augment the antidepressant effects of serotonin uptake inhibitors (i.e., SSRIs and low dose venlafaxine) and to treat their adverse effects. To put this discussion in perspective, a few comments about the effects of SSRIs and venlafaxine may be helpful. These antidepressants are believed to work by increasing serotonin availability to the various serotonin receptors in the brain by slowing the neuronal reuptake of serotonin after its release. Thus, these drugs work as indirect serotonin receptor agonists. While SSRIs are "selective" in terms of directly affecting only the serotonin uptake pump, they are not "selective" in terms of their agonism of serotonin receptors. They increase serotonin availability to all serotonin receptors. Agonism of the 5-HT1A receptor is currently believed to be the mechanism mediating the antidepressant efficacy of these drugs. Conversely, agonism of the 5-HT2A, 5HT2C, and 5-HT3 receptors may principally mediate the adverse effects of these drugs: sleep disturbance, anxiety and weight gain, and nausea/loose stools/vomiting, respectively. 7

Mirtazapine at antidepressant concentrations blocks the 5-HT2A, 5-HT2C, and 5-HT3 receptors. Thus, the combination of this drug plus an SSRI or venlafaxine could simultaneously treat the adverse effects of these drugs while increasing the availability of serotonin to the 5-HT1A receptor, the putative mechanism mediating their antidepressant efficacy. Mirtazapine also blocks the alpha-2 adrenergic receptor (Figure 1). Thus, mirtazapine could act like yohimbine, another alpha-2 adrenergic antagonist, to treat sexual dysfunction caused by serotonin uptake inhibitors. However, that potentially desirable effect may be offset by its blockade of the histamine-1 receptor (you may simply be too tired to be frisky). Alpha-2 adrenergic antagonism also promotes the release of serotonin. That coupled with serotonin uptake inhibition could increase serotonin availability postsynaptically. That could either be beneficial (e.g., increased antidepressant efficacy) or adverse (e.g., serotonin syndrome) depending on the magnitude of the increase and at what postysynaptic receptors it occurs.

To address this issue, we conducted a study to determine what happens when patients who have been on the SSRI, fluoxetine, are immediately switched to mirtazapine. 12 Fluoxetine was used in this study for two reasons. First, it persists for weeks in the body even after abrupt discontinuation. For that reason, patients switched from fluoxetine to other drugs are actually being treated with both drugs for weeks after the switch, even though they and their physicians may not consider this fact when interpreting their response. Second, due to its inhibition of multiple cytochrome P450 enzymes, fluoxetine might interact both pharmacokinetically and pharmacodynamically with mirtazapine. 6

As expected, there was an interval of several weeks when these patients had measurable and pharmacologically relevant plasma concentrations of mirtazapine and fluoxetine plus norfluoxetine. None of the patients developed the serotonin syndrome and their adverse effects were qualitatively and quantitatively the same as those seen in patients on mirtazapine, 15 mg/day, alone. As also expected, fluoxetine did not appreciably alter the concentration of mirtazapine consistent with the fact that mirtazapine has multiple pathways for its elimination. 13

Mirtazapine, like imipramine, may have a curvilinear dose-response curve. There is some suggestion that sedation is more pronounced on low rather than high dose mirtazapine therapy (15 versus 30 mg/day or more). This suggestion is principally based on the fact that there was a higher incidence of sedation in the American trials, which used lower doses, than in the European trials, which used higher doses of mirtazapine. There may be other reasons for this finding but that discussion is beyond the scope of this paper. Suffice it to say that the multiple actions of mirtazapine suggest the following theoretical explanation for why this otherwise paradoxical observation might be true. The sedative effect of mirtazapine at low doses is consistent with its high affinity for the histamine-1 receptor. Given that mirtazapine binds more avidly to that site of action than to sites capable of mediating relief from a depressive episode (Figure 1), sedation occurs at doses of mirtazapine below those needed for antidepressant efficacy (i.e., less than 15 mg/day). However, higher doses of mirtazapine result in the blockade of the alpha-2 adrenergic receptor, which produces an alerting or arousal effect just like yohimbine and just the opposite of the sedation produced by the alpha-2 adrenergic agonist, clonidine. Thus, mirtazapine most likely causes sedation at low doses (i.e., concentrations) by preferentially blocking the histamine-1 receptor, while at higher doses (i.e., concentrations), mirtazapine blocks the alpha-2 adrenergic receptor, which theoretically could reduce its sedating effects to some degree. A fixed dose trial or another type of prospective study would be needed to rigorously test this concept.

The first target affected by nefazodone is the 5-HT2A receptor (Figure 1). As the concentration of nefazodone increases, it sequentially engages the alpha-1 adrenergic receptor and then the serotonin uptake pump (Figure 1). There is almost an order of magnitude difference between nefazodone's binding affinity for the 5-HT2A receptor and its affinity for the serotonin uptake pump. Moreover, nefazodone is converted into a triazolodione metabolite, which is over 100 times more potent as a 5-HT2A receptor blocker than an uptake pump inhibitor. 14 While this metabolite is ten times less potent than the parent drug as a 5-HT2A blocker, its trough concentrations under steady-state dosing conditions are ten times higher than that of the parent drug, consistent with its longer half-life (24 versus 4 hours). 15 Based on these facts, it should be possible to achieve concentrations of the parent drug nefazodone and its triazolo metabolite that cause substantial and sustained blockade of the 5-HT2A receptor without producing substantial and sustained inhibition of the serotonin uptake pump.

As with the SSRIs and venlafaxine, 16 human studies using platelets as a surrogate measure for central serotonin uptake inhibition have been done with nefazodone to examine its dose-dependent effects on this mechanism. Nefazodone at a dose of 300 mg/day for 14 days produces 20%-40% inhibition of serotonin uptake inhibition in comparison to the 70%-80% inhibition produced by the SSRIs and venlafaxine at their respective, lowest usually effective doses. 10,17-19

The degree of serotonin uptake inhibition produced by nefazodone, 300 mg/day, relative to the SSRIs and venlafaxine, is consistent with its in vitro binding affinity and its drug concentration. While nefazodone is capable of inhibiting the serotonin uptake pump, it is relatively weak in terms of its binding affinity. For example, nefazodone's binding affinity is three orders of magnitude weaker than paroxetine or sertraline. 20 Given that difference, some may find it surprising that nefazodone produces any inhibition of the serotonin uptake pump. It does so for the same reason that bupropion inhibits the dopamine uptake pump at its usually effective dose. 21 The reason is that the concentrations of nefazodone achieved within its clinically relevant dosing range are three orders of magnitude higher than the concentrations of the SSRIs (Table 1). 10

In fact, the low binding affinity of nefazodone for the serotonin uptake pump may partly explain why such relatively high concentrations of nefazodone are needed to achieve clinical efficacy as an antidepressant.

Parenthetically, the same point was made in the preceding column about concentrations of bupropion and its metabolites relative to their binding affinity for the dopamine and norepinephrine uptake pumps. 21 Nevertheless, the degree of serotonin uptake inhibition produced by nefazodone, 300 mg/day, is probably not sufficient in and of itself to produce an antidepressant response. The basis for this inference comes from fixed dose studies with citalopram, paroxetine, and venlafaxine, in which it was found that those antidepressants, at doses that should produce less than 70% inhibition of serotonin uptake inhibition, were not superior to placebo in the treatment of patients with major depression.10

Thus, the platelet uptake inhibition studies with nefazodone provide a heuristic explanation for several of the ways in which the clinical pharmacology of nefazodone differs from that of the SSRIs and venlafaxine.

First, at 300 mg/day, nefazodone does not appear to produce as robust an antidepressant response on average as do the lowest usually effective doses of SSRIs and venlafaxine. 15 This statement is based on the magnitude of the reduction of depressive severity as measured by the Hamilton Depression Rating Scale (HDRS) 25 score in the antidepressant group versus its parallel placebo control group in double-blind, efficacy trials.

Second, nefazodone, like venlafaxine and in contrast to the SSRIs, has an ascending dose-antidepressant response curve. 15 The difference is that, at its lowest recommended dose, venlafaxine produces a reduction in HDRS scores that is comparable to that seen with the SSRIs, whereas nefazodone, as already mentioned, does not. When the dose of nefazodone reaches the upper end of its recommended dose range, the reduction is comparable and perhaps even superior to the reduction produced by the SSRIs, but not as great as occurs with the highest dose of venlafaxine. 15

Third, low-dose nefazodone treatment causes a lower incidence of sexual dysfunction than occurs on sertraline and most likely the other SSRIs and venlafaxine. 26 As is often said, your strength is often also your weakness. Thus, the lower degree of serotonin uptake inhibition produced by low-dose nefazodone treatment relative to the SSRIs and venlafaxine could account for both its decreased antidepressant efficacy and its lower incidence of sexual dysfunction relative to these other antidepressants.

Several inferences can be drawn from these observations. First, the blockade of 5-HT2A receptors (i.e., the predominant action of nefazodone at 300 mg/day) is not as robust an antidepressant mechanism of action as is serotonin uptake inhibition. That inference is further supported by the fact that antidepressant clinical trials programs with more than one relatively pure 5-HT2A blocker have not shown superior efficacy over placebo. Second, the fact that nefazodone at higher doses is comparable and perhaps even superior to the SSRIs in terms of HDRS score reduction suggests that 5-HT2A blockade combined with serotonin uptake inhibition may be superior to either mechanism alone. That may either reflect a synergistic action, or it may be that 5-HT2A blockade reduces adverse effects due to serotonin uptake inhibition that either mimic depressive symptoms (e.g., insomnia) or lead to treatment discontinuation before efficacy is achieved. Conceivably, a drug with a smaller gap between its binding affinity for the 5-HT2A receptor versus the serotonin uptake pump might be more efficacious or better tolerated than either nefazodone or the SSRIs. Such inferences can lead to further discovery work to develop and test such a compound as an antidepressant. Third, these observations indicate why dose titration is more necessary with nefazodone than with most of the SSRIs to obtain an adequate antidepressant response. Unfortunately, the nonlinear pharmacokinetics of nefazodone make such dose titration more difficult than would be expected with a drug with linear pharmacokinetics. Further discussion of this topic is beyond the scope of this column.

Imipramine, mirtazapine, and nefazodone are at the opposite end of the spectrum from the SSRIs (e.g., sertraline) or the NSRIs (e.g., desipramine or reboxetine) in terms of number of mechanisms of action that are affected at concentrations achieved in the usual patient taking these drugs at their respective antidepressant doses. To the best of our knowledge, the behavioral pharmacology of the SSRIs and the NSRIs is constrained to the effects mediated by their single mechanism of action, serotonin uptake inhibition and norepinephrine uptake inhibition, respectively. In contrast, the pharmacology of imipramine, mirtazapine, and nefazodone is richer or more varied or more complicated (i.e., pick the spin you prefer) than that of the SSRIs as a result of their effects on multiple mechanisms of action. That pharmacology includes both desired and undesired effects, which are often mirror images of the same phenomenon. It is for this reason that drug therapy is rarely, if ever, foolproof and why proper education is needed to prescribe and monitor medications.

The goal of this series of columns has been to help clinicians better understand the differences in the in vitro pharmacology of the various antidepressants as they relate to their clinical pharmacology in patients. This knowledge may help clinicians optimize their selection of an antidepressant for a given patient by matching the pharmacology to the symptom profile of the patient. The clinician can also use this knowledge to help guide the choice of an alternative antidepressant if a patient either does not benefit from or does not tolerate treatment with the first antidepressant chosen.

In my next column, I will present tables that summarize the adverse effect profile of the antidepressants that have been reviewed in this series of columns. These tables will further demonstrate how our ability to predict the pharmacology of a drug depends on understanding the relationship between its pharmacodynamics and its pharmacokinetics.


Which Antidepressants Cause the Least Sexual Side Effects?

Sexual side effects and one&rsquos libido are an important issue when it comes to antidepressant medications and depression itself. All too often, this issue is ignored when antidepressants are prescribed by a family physician or general practitioner. Yet sexual side effects are important enough that they should be addressed.

Although the focus of most depression treatment is on the alleviation of symptoms commonly associated with depression, some people are more sensitive to sexual side effects than others in certain types of antidepressant medications. For some people, their sex life may also be just as important as alleviating the symptoms of depression.

Research on Sexual Side Effects and Antidepressants

A 2001 study out of the University of Virginia examining the prevalence of sexual dysfunction among antidepressant users reveals that while the drug classes known as selective serotonin reuptake inhibitors (SSRIs, such as Paxil or Zoloft) and serotonin and norepinephrine reuptake inhibitors (SNRIs, such as Effexor and Cymbalta) were associated with a higher rate of sexual dysfunction, other antidepressants were associated with significantly lower rates, namely bupropion (Wellbutrin) and nefazodone (Serzone). These data suggest that sexual dysfunction may be related to serotonergic antidepressant therapy.

Wellbutrin, the brand name of bupropion, had the lowest overall rate of sexual dysfunction. It was associated with a rate of 22% of the overall population. The sustained release formulation fared almost as well with a rate of 25%. In contrast, the SSRIs (Prozac, Paxil, Zoloft and Celexa), venlafaxine (Effexor) and mirtazapine (Remeron) averaged about 40%. When subjects were removed who had other probable causes of sexual dysfunction, the results were even better. Wellbutrin&rsquos rate dropped to 7% with the other medications dropping to between 23-30%.

Wellbutrin is a norepinephrine and dopamine reuptake inhibitor (NDRI). It is contraindicated in patients with a seizure disorder or those taking Zyban, which also contains bupropion. It is also contraindicated for those with a diagnosis of an eating disorder such as bulimia or anorexia and for those currently taking an MAOI.

Results were presented on May 8, 2001 at the American Psychiatric Association annual meeting.

What This Means

People who are sensitive to sexual side effects should ask their doctor about switching to an antidepressant such as Wellbutrin or Serzone, which have lower sexual side-effect profiles than other commonly prescribe antidepressants.


Four Newer Antidepressants: Should You Use Them?

Since 2011, 3 new antidepressants have been approved by the FDA, and another (ketamine) has been generating buzz as a potential off-label medication for depression. In this article, well take a step back and review the data on vilazodone (Viibryd), levomilnacipran (Fetzima), vortioxetine (Brintellix), and ketamine.

Vilazodone (Viibryd)

Vilazodone was approved by the FDA in January of 2011, making it the oldest of the newer antidepressants. Those who like tracking mechanisms of action are calling vilazodone a SPARI, which stands for serotonin partial agonist/reuptake inhibitor. The drug inhibits reuptake of serotonin (like SSRIs) and has partial agonism at 5-HT1A receptors (like buspirone). So, theoretically, giving your patients vilazodone is similar to giving them both an SSRI and buspironeat the same time. Is that a good thing? Nobody knows for sure. In the STAR*D trial, buspirone had a cameo appearance in one of the steps, being used as an augmenter of citalopram, and it worked as well as bupropion augmentationa finding that may or may not have any relevance to vilazodone.

When the drug was first approved, the word on the street was that it (1) may work faster than other antidepressants, (2) may have fewer sexual side effects, and (3) may be more effective for anxiety. We were skeptical of these claims then, as was the FDA (see TCPR, April 2011 and http://carlatpsychiatry.blogspot.com/2011/10/fda-slams-viibryd-better-sexual-profile.html). But new datahave accumulated since then. Well rely mainly on a review published in 2015, which included 4 later-stage and post-marketing studies, as opposed to the pre-approval studies that the FDA reviews (Hellerstein DJ et al, Core Evid 201510:4962).

Onset of action

The idea of faster onset of action was originally based on one piece of animal data and one piece of human data. The animal data showed that vilazodone quickly enhanced serotonin transmission in rats via 2 distinct mechanisms: 5-HT1A partial agonism and regular serotonin reuptake. In the human study, vilazodone showed statistically significant reduction in depression scores compared to placebo quite early, by week 1, although there was no active drug comparison (Rickels K et al, J Clin Psychiatry 200970(3):326333).

Two more recent studies showed greater improvement versus placebo as early as week 2 (Croft HA et al, J Clin Psychiatry 201475(11):e1291 e1298 Mathews M et al, Int Clin Psychopharmacol 201530(2):6774). However, antidepressant response at 2 weeks is not unique to vilazodone. Early improvement is the rule and not the exception for many antidepressants (Szegedi A et al, J Clin Psychiatry 200970(3):344353). In addition, when researchers focused on remission instead of response, vilazodone took 6 full weeks to outperform placebo. The bottom line is that there is no convincing evidence that vilazodone has a faster onset of action than any of its competitors.

Sexual side effects

Early studies suggesting a cleaner sexual side effect profile for vilazodone were problematic. First, there was no SSRI comparator, which would have been necessary to make any claims that vilazodone had an advantage over other agents. Second, most of the patients enrolled had preexisting sexual dysfunction before being randomized to vilazodone or placebo. One can argue that this design has the advantage of being generalizable to many of our patients, who have underlying sexual dysfunction due to depression or age, for example. On the other hand, its akin to testing whether a drug has a headache side effect by giving it to a bunch of people who already had headaches. Any new onset headaches would be obscured by the pathology already there. And indeed, in the company-funded study, treatment with vilazodone didnt worsen the already high burden of sexual side effectsin fact, it was no different from placebo, both of which resulted in a slight improvement in sexual functioning (Rickels K et al, J Clin Psychiatry 200970(3):326333).

In a more recent industry-funded post-hoc analysis of patients with normal baseline sexual function who were randomized to vilazodone, citalopram, or placebo, there were no significant differences in onset of new sexual side effects. The rates were: placebo: 12% vilazodone 20 mg/day: 16% vilazodone 40 mg/day: 15% and citalopram 40 mg/ day: 17% (Mathews MG et al, Abstract 45, ASCP 2014 http://ascpmeeting.org/wp-content/uploads/2014/06/Poster-Session-Book-Final-6-29.pdf). There was also no significant difference among those who had baseline sexual dysfunction: 33% of patients on placebo, 35% on vilazodone 20 mg/day, 30% on vilazodone 40 mg/ day, and 28% on citalopram patients improved to normal sexual function by the end of the study.

According to the website ClinicalTrials.gov, there are ongoing studies of vilazodone addressing the sexual function issue. Until those results are published, we continue to consider the low sexual side effect claims as unsubstantiated.

Efficacy in anxiety

Theres a theoretical argument to be made that vilazodones 5-HT1A partial agonism might give it special anti-anxiety power. The only clinical trial evidence thus far is based on comparisons with placebo. As is true for many other antidepressants, vilazodone reduces scores on the Hamilton Anxiety Rating Scale more than placebo (Rickels K et al, J Clin Psychiatry 200970(3):326 333 Khan A et al, J Clin Psychiatr 201172(4):441447). Another analysis of these data found that vilazodone may be more effective for the subgroup of anxious depressed patients than for the non-anxious depressed (Thase ME et al, Int Clin Psychopharmacol 201429(6):351356). Promising, but wed need data comparing this medication with other antidepressants to be convinced that it has an advantage.

TCPR Verdict: Based on this second look at vilazodone, we dont see any new evidence that it works faster, has fewer sexual side effects, or is preferred in depressed patients with significant anxiety. We consider this a second-line antidepressant to be used after generics have failed.

Levomilnacipran (Fetzima)

Levomilnacipran was approved by the FDA in July 2013 for major depressive disorder. It is the close chemical cousin (an enantiomer) of milnacipran (Savella), approved in the U.S. in 2009 for fibromyalgia and approved for depression in other countries. Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI), which puts it in the same class as duloxetine (Cymbalta), venlafaxine (Effexor XR), and desvenlafaxine (Pristiq). However, levomilnacipran is more selective for inhibiting norepinephrine reuptake than the othersstudies have shown that it has a 15-fold higher selectivity for norepinephrine than for serotonin. This selectivity disappears at higher doses.

But does norepinephrine selectivity mean anything clinically? Some researchers have hypothesized that there is a norepinephrine deficit depression, associated with poor concentration, inattention, low motivation, lack of energy, and cognitive impairment. This might be distinct from a serotonin deficit depression, more associated with anxiety, appetite disturbances, and suicidality (Moret C et al, Neuropsychiatr Dis Treat 20117Suppl1:913 Nutt DJ, J Clin Psychiatry 200869SupplE1:47). It would be nice if we could someday identify depressive subtypes that respond to specific medications, but the evidence for this norepinephrine/ serotonin division is still indirect and preliminary.

Nonetheless, these speculations provide promotional talking points for reps, who may argue that their drug has a special norepinephrine-based power to improve impaired daily functioning. Lets look at the data.

Evidence on improving functioning

According to a recent meta-analysis, 4 out of 5 double-blind, placebo-controlled, short-term studies found that levomilnacipran was more effective than placebo for overall depressive symptoms (Montgomery SA et al, CNS Spectr 20145:19). The average response rate was 46% for levomilnacipran (vs. 36% on placebo) and the average remission rate was 28% (vs. 22% on placebo).

These studies also assessed change in functionality as a secondary measure. This was done using the Sheehan Disability Scale (SDS), a self-rating scale which asks about work/school, social life, and family life to measure functionality. Each of the three domains is scored from 0 (unimpaired) to 10 (extremely impaired). Any domain with a score of 5 or higher means significant functional impairment. So an SDS score of <12 total and <4 on all subscales indicates functional responders. An SDS score of <6 total and <2 on all subscales means functional remitters.

The meta-analysis reported a mean change in SDS score that was significantly greater with levomilnacipran compared to placebo but the actual difference in score was small, only a mean of 2.2 points better than placebo, (Sambunaris A et al, Int Clin Psychopharmacol 201429(4):197205). The pooled response ratethat is, the percent of patients who functioned better at the end of the trialwas 39% for levomilnacipran vs. 29% on placebo, and the pooled remission rate was 22% vs. 15% on placebo.

Of course, the skeptic in us points out that any medication that eases depression is likely to also improve functioning. It may be that all antidepressants, regardless of their mechanisms of action, are just as effective as levomilnacipran for impaired functioning. Unfortunately, the company has not compared its drug with anything more robust than placebo, so we dont know the answer yet.

An interesting secondary, post-hoc analysis of 1 of the 10-week placebo-controlled levomilnacipran studies looked at individual items in the major depression scales. The results didnt support that levomilnacipran was better at any particular neurotransmitter profile of symptoms. Instead, the drug improved the same types of symptoms targeted by other antidepressants. So its unclear whether the higher selectivity for norepinephrine truly relates with any significant clinical outcome (Montgomery SA et al, Int Clin Psychopharmacol 201429(1):2635).

TCPR Verdict: Levomilnacipran is an SNRI with especially strong reuptake inhibition of norepinephrine as opposed to serotonin. But whether it has any clear efficacy advantages over its competitors is not clear.

Vortioxetine (Brintellix)

Vortioxetine was approved by the FDA in September of 2013 for major depression. Its considered a multimodal agent, meaning that it acts not only as a serotonin reuptake inhibitor but also affects several other serotonin receptors. It is an agonist of 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3 and 5-HT7 receptors.

How well does vortioxetine work? A recent review of published and unpublished trials of the medication found 14 short-term randomized trials (6 to 12 weeks) eight of which were positive, five were negative, and one was considered failed because neither vortioxetine nor the active control, duloxetine, showed symptomatic improvement over placebo (Kelliny M et al, Ther Clin Risk Management 201511:11921212). Some studies compared vortioxetine to placebo, others to duloxetine or venlafaxine. Vortioxetine showed no clear superiority over active controls in measures of response or remission. So while vortioxetine has a distinctive pharmacological profile (Citrome L, Int J Clin Pract 201468(1):6082), it is no more effective for core depressive symptoms than standard antidepressants.

The approved dose of vortioxetine is 1020 mg/day. Sexual dysfunction has been reported to be minimal, but most premarketing trials relied solely on spontaneous reporting of adverse effects, which is known to underestimate their frequency (Cosgrove L et al, Account Res 2016 [Epub ahead of print]), and in one of the few trials that used a scale to measure effects on sexual performance, the authors concluded that the sample number is too small to draw any conclusions (Mahableshwarkar AR et al, J Clin Psychiatry 201576(5):583591).

Is vortioxetine a smart pill?

As we know, diminished ability to think or concentrate is one of the DSM-5 criteria for major depression. Specific domains such as executive function, processing speed, attention, and learning and memory, have been found to be deficient during acute major depressive disorder (MDD) (Hammar A and Ardal G, Front Hum Neurosci 20093:26).

In an effort to get a leg up on its competitors, the manufacturer has done studies showing that vortioxetine improves patients performance on experimental cognitive tasks. Preclinical trials found that subjects on vortioxetine did better than those on duloxetine on the Digit Symbol Substitution Task (DSST), a measure of psychomotor speed (Gonzalez-Blanch C et al, Arch Clin Neuropsychol 201126(1):4858). They then used the same outcome in 2 larger studies, each with 602 subjects. After 8 weeks, subjects on vortioxetine had higher scores on the DSST compared to those on placebo or those taking duloxetine, but by only 1.5%3.0% (2 to 4 points on a 133-point scale) compared to placebo, and <0.5% (0.5 points) compared to duloxetine. On the strength of these studies, the company is applying for a new cognitive dysfunction in MDD indication. An FDA expert advisory panel recommended the approval in February, but just as we were sending this issue to press, the agency announced it would deny an expanded indication for cognitive dysfunction (http://www.biopharmadive.com/news/in-reversalfda-denies-cognitive-dysfunction-labelexpansion-for-brintelli/416536/).

We assume that the FDAs skepticism was related to a couple of important questions: First, do improvements on the DSST score translate into functional improvements that we (or our patients) would recognize clinically? Second, is vortioxetine any better than other antidepressants for improving cognition in depression?

In terms of the meaningfulness of its pro-cognitive properties, a recent meta-analysis found that while vortioxetine improves performance in the DSST, it didnt help patients on 3 other cognitive tests. These include the Stroop test (a measure of cognitive control), the TrailMaking Test B (executive function), and the Rey Auditory Verbal Learning Test (delayed recall) (Rosenblat JD et al, Int J Neuropsychopharmacol 201519(2).pii: pyv082.doi:10.1093/ijnp/pyv082). As a smart pill, vortioxetines effects seem limited to one specific testwhich doesnt improve our confidence in its efficacy.

Finally, are the cognitive benefits of vortioxetinehowever modest they may bea direct pro-cognitive effect? Or do they indirectly follow from vortioxetines role as an antidepressant, thus implying that it wont perform better than any other treatment that eases depression? This question has not yet been fully answered, although one manufacturer-sponsored trial claims that the higher DSST scores were independent of its antidepressant effect (Mahableshwarkar AR et al, Neuropsychopharm 201540(8):20252037). Similar claims have also been made for duloxetine (Greer TL et al, Dep Res Treat 2014. Published online 2014 Jan 19. doi: 10.1155/2014/627863), but other antidepressants simply havent been studied for their cognitive benefits.

TCPR Verdict: Will Brintellix make your patients Brintellectuals? The FDA is skeptical, and so are we.

Ketamine is not FDA approved for depression, but rather for preoperative general anesthesia. And it doesnt act on serotonin, norepinephrine, or dopamine instead, its an antagonist of the NMDA subtype of the glutamate receptor. It has long had illicit popularity in the party and rave scene under the nickname special K. Of relevance to psychiatrists, ketamine has been touted as a potential fast-acting miracle antidepressant, and many clinicians are already offering it off-label to their patients in pop-up ketamine clinics. Should you jump on the ketamine bandwagon?

The ketamine antidepressant data

As of late 2015, nearly a dozen randomized clinical trials of intravenous ketamine for the treatment of depression had been published (DeWilde KE et al, Ann NY Acad Sci 20151345:4758). These include some placebo-controlled trials, in addition to some open-label trials and a few trials with an active control (usually midazolam [Versed]). All showed, on average, a statistically significant responsedefined as a 50% reduction in MADRS or Hamilton Rating Scale for Depression (HAM-D) symptomscoreswithin 24 hours. Response rates have ranged from 40% to 70%. Some studies used only a single dose, with an antidepressant effect lasting up to 72 hours (even longer in some studies), while others involved repeated IV administrations over 2 weeks. The typical ketamine dose was 0.5 mg/kg given over a 40-minute periodas opposed to the anesthetic dose, which ranges from 1.04.5 mg/kg IV usually given over one minute.

Other studies have found that single infusions reduce suicidal ideation at 4 and 24 hours post-infusion (Price RB et al, Biol Psychiatry 200966:522526). Investigators are now trying to identify subgroups who are more likely to respond to ketamine. There arent enough data yet to predict response, but some potential positive indicators include a family history of alcoholism, comorbid anxiety, or an elevated body mass index (Niciu MJ et al, J Clin Psychiatry 201475:e417423).

Ketamine in the office?

So if it provides such rapid relief to some people who have been refractory to other treatments, why hasnt ketamine caught on? One major hurdle, of course, is the fact that its an intravenous medication, making it much more complicated to prescribe than a pill. Because of potential, though rare, side effects such as an acute hypertensive crisis, the IV infusion should take place in a medical office equipped with vital sign monitoring, airway equipment, oxygen, and a crash cart. Some even advise the presence of a trained anesthesiologist (Sisti D et al, Curr Psychiatry Rep 201416:527). These requirements likely explain the high outof-pocket costs (up to $500$750 per infusion) for this off-label procedure at the handful of ketamine clinics that have popped up nationwide over the last few years. Other potential adverse effects, like an uncomfortable dissociative experience, as well as long-term cognitive impairment and the risk of diversion or recreational abuse of ketamine, must be considered.

Furthermore, no one really knows how long to provide the treatment. In the 2-week trials described above, which involved 6 infusions, relapse rates were as high as 55% to 89% in the month following treatment (Newport DJ et al, Am J Psychiatry 2015172:950966). No maintenance strategy has been described, and no other medications have been shown to extend ketamines antidepressant effect.

Finally, its still not clear that the standard 0.5 mg/kg intravenous dose is the best dose. This dose was chosen, in part, because it produces few side effects these are typically transient dissociative symptoms (I feel like Im floating) or hallucinations during the infusion. While these effects are short-lived, they have also been positively associated with a treatment response (Luckenbaugh DA et al, J Affect Disord 2014159:5661). Thus, dissociative effects may predictor may even be responsible forthe antidepressant effect. If this is true, it may be hard to find a dose that minimizes unpleasant psychoactive effects while also producing a robust antidepressant effect. Then again, some practitioners are deliberately using higher doses of ketamine,sometimes in intramuscular or oral forms, in order to induce a psychedelic state, which they see as a necessary component of healing (Dakwar E et al, Drug Alc Depend 2014136:153157).

Pharmaceutical companies have eagerly embraced the ketamine story, in hopes of developing a similar drug without ketamines reputation and its pesky DEA Schedule III designation. But the options are limited. AstraZeneca tested one compound, lanicemine, but quietly backed out after it failed a Phase IIb trial in 2015. Another compound called GLYX-13 (recently renamed rapastinel), a partial agonist at another site on the NMDA receptor, has been effective in reducing HAM-D scores relative to placebo at some doses, and further research is ongoing. Other labs are studying the tuberculosis drug Dcycloserine, another NMDA modulator, as well as other agents. The closest thing to ketamine in the commercial pipeline is Janssens intranasal S-ketamine (an enantiomer of ketamine), currently in phase II trials.

Of course, if you want to explore this territory on your own, IV ketamine is readily available. It can be compounded into oral, sublingual, and intranasal forms. But its use in depression remains strictly off-label and, at this time, must be seen as experimental. As more data become available and protocols are published and refined, it may be worth your time and effort to add it to your repertoire.

TCPR Verdict: Ketamine looks promising for extremely rapid relief of depressionbut the effects are short-lived, and any antidepressant that requires a crash cart nearby is not likely to become a blockbuster.


Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data

Michelle D. Colvard Key differences between Venlafaxine XR and Desvenlafaxine: An analysis of pharmacokinetic and clinical data. Mental Health Clinician 1 January 2014 4 (1): 35–39. doi: https://doi.org/10.9740/mhc.n186977

Venlafaxine XR and its major active metabolite, desvenlafaxine, are serotonin-norepinephrine reuptake inhibitors. Both are FDA-approved for the treatment of major depressive disorder and have essentially the same pharmacologic and pharmacokinetic profiles however, the recommended dosing is notably different. The FDA approved recommended starting and maintenance dose for desvenlafaxine is 50 mg daily, while venlafaxine XR requires titration from 37.5 mg daily to the maintenance dose of 150 - 225 mg daily. The dose recommendation for desvenlafaxine is based on results from 8-week acute-phase clinical trials, but complete therapeutic response is not always achieved in this short time period. Venlafaxine XR relies on CYP2D6 for conversion to desvenlafaxine while desvenlafaxine has no significant metabolism by CYP2D6 at recommended doses. Both venlafaxine XR and desvenlafaxine have limited clinically significant drug interactions. The most striking difference between the two products is cost.

Venlafaxine extended release (XR) was the first once daily serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD) by the Food and Drug Administration (FDA) in 1997. 1 Approximately ten years later desvenlafaxine (O-desmethylvenlafaxine), the primary major active metabolite of venlafaxine, also joined the market for this indication in the form of desvenlafaxine succinate (Pristiq ® ). 2 The FDA also recently approved generic desvenlafaxine fumarate and the free base form of desvenlafaxine as both a generic and brand name (Khedezla ER) products. 3–5 This review will focus on desvenlafaxine succinate as efficacy, pharmacokinetic, and safety data are mostly available for this product.

Venlafaxine and desvenlafaxine are essentially pharmacologically equivalent. 6 , 10 Both are potent and selective inhibitors at serotonin and norepinephrine transporters with small differences in binding affinity measured by Ki value (lower Ki value indicates more selective binding). 2 , 6–8 The Ki values for serotonin reuptake pumps are 40.2 nM and 82 nM for desvenlafaxine and venlafaxine, respectively. 7 , 8 Ki values for norepinephrine reuptake pumps are 558.4 nM and 2480 nM for desvenlafaxine and venlafaxine, respectively. 7 , 8 Theoretically, higher binding affinity for desvenlafaxine versus venlafaxine at norepinephrine reuptake pumps could translate into differences in efficacy but this has not been validated in head-to-head clinical trials. Neither agent has significant affinity for cholinergic, alpha-adrenergic, or histaminergic receptors. 2 , 6 No clinically significant differences in adverse effects or tolerability have been identified in clinical trials. A detailed comparison of adverse effects and tolerability among SNRIs was recently published by Alipour. 9

While there may be subtle variances in receptor binding affinity and adverse effects, more notable differences between the two medications are related to metabolism and FDA approved dosage. 2 , 6 Because venlafaxine is primarily metabolized by cytochrome P450 (CYP) 2D6, there is concern that alterations in CYP2D6 activity could negatively impact efficacy and tolerability. 6 For this reason, it has been speculated that desvenlafaxine may be preferred in patients with drug-drug interactions and genetic polymorphisms which affect CYP2D6. 11–17 Furthermore, the fact that desvenlafaxine has the same starting and maintenance dose while venlafaxine XR should be gradually titrated may make desvenlafaxine a more appealing choice for some providers and patients. 2 , 6 The clinical impact of these differences has not been fully described. This article will review the data related to differences in metabolism and dosing between venlafaxine XR and desvenlafaxine to describe clinical significance.

Pharmacokinetic Comparison

At least 92% of a single dose of venlafaxine XR is absorbed and subsequently undergoes presystemic hepatic metabolism. It is estimated that 55% of a single dose is converted to desvenlafaxine via CYP2D6-mediated phase I oxidative metabolism. CYP1A2, CYP3A4, and CYP2C19 are responsible for the formation of other minor inactive oxidative metabolites including N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. 6 Unlike venlafaxine, desvenlafaxine is primarily inactivated via phase II glucuronidation with minimal oxidative metabolism via CYP3A4 to N,O-didesmethylvenlafaxine. 2 Both venlafaxine XR and desvenlafaxine are primarily renally eliminated as varying concentrations of unchanged drug, active, and inactive metabolites. 2 , 6 Because venlafaxine XR relies on CYP2D6 for conversion to the major active metabolite, there has been much investigation of the differences in its pharmacokinetic parameters and clinical efficacy among patients with CYP2D6 polymorphisms (polymorphisms in the CYP2D6 gene can result in phenotypes with varying levels of metabolic activity). 6 Extensive (EM) and intermediate metabolizers (IM) are considered to have ‘normal' levels of enzyme activity while ultrarapid (UM) and poor metabolizers (PM) have significantly increased or decreased levels of enzyme activity, respectively. 18 While the majority of the population are EMs, up to 7% of Caucasians are CYP2D6 PMs. 19 Some have concluded that desvenlafaxine may be preferred in this population since it does not require CYP2D6 for clinical activity or clearance unlike many other antidepressants including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, duloxetine, and venlafaxine. 11 , 13 , 16

In an attempt to quantify the effect of differences in metabolism between medications, the variances in medication metabolite plasma concentrations among CYP2D6 phenotypes have been measured. Studies evaluating plasma concentrations of venlafaxine and desvenlafaxine following administration of venlafaxine XR have clearly and consistently found the desvenlafaxine/venlafaxine ratio to be significantly lower in PMs when compared to EMs. 11 , 13 , 16 However, no difference in desvenlafaxine serum concentrations was found between PMs versus EMs following administration of desvenlafaxine in these studies. Of note, the sum of venlafaxine and desvenlafaxine did not differ between PM and EM groups receiving venlafaxine XR. 11 , 13 , 16 Considering that venlafaxine and desvenlafaxine are “pharmacologically approximately equiactive and equipotent” and clinical efficacy results from the net contribution of both compounds, one would not expect there to be clinically meaningful differences in efficacy and tolerability between PMs and EMs. 6

Studies have examined the possibility of decreased venlafaxine tolerability and efficacy in PMs versus EMs. One retrospective review that included patients who experienced adverse effects or insufficient clinical response to venlafaxine IR or XR found CYP2D6 PMs were significantly more likely to be on lower doses of venlafaxine (n=5100% taking 75 mg) versus other phenotypes (n=33 78.8% taking ≥150 mg). 14 Reasons for venlafaxine discontinuation or dose decrease in PMs included increased anxiety, insomnia, decreased appetite, somnolence, and fatigue. This finding may support the theory that CYP2D6 PM phenotype contributes to varied patient treatment response with venlafaxine however, demographics as well as initial dosing and dosing titrations were not consistent between groups. Prospective randomized trials are needed to confirm this conclusion. Another retrospective review included German patients who experienced adverse effects or insufficient clinical response while taking CYP2D6 dependent antidepressants (i.e., fluoxetine, n= 3 paroxetine, n=2 and fluvoxamine, n=1 amitriptyline, n=9 doxepin, n =5 venlafaxine, n=3 maprotiline, n=2 clomipramine, n=1 imipramine, n=1 trimipramine, n=1). 15 There was a significantly higher incidence of CYP2D6 PMs (28%) among those who experienced adverse effects or insufficient clinical response while taking CYP2D6 dependent antidepressants than found in the general population (7%). Unlike venlafaxine, other antidepressants included in this review do not have pharmacologically equivalent active metabolites. Therefore, increased side effects are expected to occur in CYP2D6 PMs as the parent drug serum concentration accumulates. Results of this review cannot be generalized to venlafaxine as statistical significance cannot be determined for the small number patients who experienced side effects on venlafaxine. Only one prospective study has demonstrated a statistically significant increased risk of side effects in PMs versus EMs taking a venlafaxine product. 12 When compared to EMs, CYP2D6 PMs taking venlafaxine IR for depression indications had a higher mean number of side effects (2.3 vs. 0.49 p<0.005) and lower mean serum sodium concentrations (138 vs. 142 mg/dL p<0.05). There does not appear to be a difference in severe side effects between the groups as the most commonly reported side effects were gastrointestinal side effects, and the difference in serum sodium concentrations does not appear to be clinically significant. 12 No significant differences in efficacy outcomes were found in these studies. 12 , 14–15 There is also one pooled analysis of four double blind, placebo-controlled trials (6 – 12 weeks) of patients with major depressive disorder that found significant differences in depression efficacy outcomes between EMs and PMs taking venlafaxine XR and IR. 11 The EMs had significantly greater improvements in change from baseline Hamilton Depression Rating Scale, 17-item (HAM-D17) and Montgomery Asperger Depression Rating Scale (MADRS) scores, HAM-D17 response rate, and MADRS response and remission rates. The HAM-D17 remission rates and incidence of side effects did not differ between the two groups. Despite the inherent limitations of this pooled analysis of clinical trials using varying venlafaxine formulations and protocols, these results suggest that CYP2D6 PMs may respond less favorably to venlafaxine XR therapy than EMs. 11 Head to head studies comparing efficacy of desvenlafaxine and venlafaxine XR in PMs are necessary to make definitive recommendations for treatment of this population. Because CYP2D6 PMs account for only 1 – 2% of African Americans 1% of Asians and up to 7% of Caucasians, it is not necessary to select desvenlafaxine over venlafaxine XR regularly to avoid intolerance or insufficient response to therapy. 19 Pharmacogenetic testing with the AmpliChip CYP450 may be helpful for some patients who experience intolerance or other difficulties with venlafaxine XR or other antidepressants. 19 Considering it costs approximately $2,000 yearly for desvenlafaxine and $150 yearly for generic venlafaxine XR (based on average wholesale price), it actually is less expensive to perform CYP2D6 phenotyping ($250 – $500) before initiating antidepressant therapy than to choose desvenlafaxine over venlafaxine for most patients. 19–20

Another potential difference between desvenlafaxine and venlafaxine XR is also related to metabolism: the risk for pharmacokinetic drug-drug interactions. Because desvenlafaxine has no significant effect on CYP2D6 at recommended doses, it is promoted as an appealing option to avoid potential drug-drug interactions with CYP2D6 substrates (e.g., many beta blockers, SSRIs, tricyclic antidepressants, opioids). However, venlafaxine XR is also unlikely to significantly affect CYP2D6 substrates. Venlafaxine IR was found to have lower inhibitory potency for CYP2D6 than any SSRI in in vitro studies. 22 Venlafaxine XR and desvenlafaxine have similar effects on substrates of CYP2D6 at recommended doses. In pharmacokinetic studies, venlafaxine IR 37.5 mg every 12 hours and desvenlafaxine 100 mg increased CYP2D6 substrate desipramine area under the curve (AUC) by 35% and 17% respectively. 2 , 6 It is interesting to note that a single dose of desvenlafaxine 400 mg increased desipramine AUC by 90%, so some CYP2D6 substrates with dose related side effects (e.g., tamoxifen, beta-blockers) may require dose reduction when combined with a higher dose of desvenlafaxine. 2 In regard to other potential mechanisms for interactions, both venlafaxine and desvenlafaxine are weak inhibitors of CYP3A4 and CYP1A2 and have minimal protein binding (27%, 30% respectively) making both agents unlikely to result in related interactions. 2 , 5 , 23 Combination with strong CYP2D6 inhibitors (i.e., paroxetine, fluoxetine, quinidine, bupropion) may impact venlafaxine XR more than desvenlafaxine, but clinical significance is unknown. 2 , 17 , 21 The combination of venlafaxine XR with a strong CYP2D6 inhibitor should result in decreased desvenlafaxine/venlafaxine ratios just as seen in patients who are CYP2D6 PMs. 6 Evidence of less favorable venlafaxine efficacy and tolerability with lower desvenlafaxine/venlafaxine ratios found in PMs is limited, and there does not appear to be a difference in serious adverse events when compared to EMs. 11–12 It is acceptable to combine venlafaxine XR with CYP2D6 inhibitors, if indicated. There are very few combinations that are likely to occur between venlafaxine XR and strong CYP2D6 inhibitors. SNRIs are not typically combined with SSRIs which leaves bupropion as the most likely interacting inhibitor.

The difference in FDA recommended dosing between venlafaxine XR and desvenlafaxine may make desvenlafaxine more appealing to some providers and patients. Desvenlafaxine is marketed as “an SNRI with a starting dose that is the proven effective dose” while venlafaxine XR requires titration to reach the maximum daily recommended dose of 225 mg. 6 , 17 However, comparison of bioavailability between venlafaxine XR and desvenlafaxine make this difference in recommended daily dosing somewhat unexpected. While the absolute bioavailability of venlafaxine XR is 45%, the bioavailability of total active drug is similar between venlafaxine XR (45% venlafaxine + 47% desvenlafaxine) and desvenlafaxine (80% desvenlafaxine). 2 , 6 This is illustrated in results from pharmacokinetic studies. Following administration of venlafaxine XR 75 mg to seven EMs, the mean (± SD) maximum plasma concentration (Cmax) and AUC were 30.1 ng/mL (17.7) and 518 (462) ng/mL for venlafaxine and 94.2 ng/mL (27.4) and 2589 (541) ng/mL for desvenlafaxine. When the same EMs were given desvenlafaxine 50 mg, the Cmax and AUC of desvenlafaxine were 84.5 ng/mL (15.4) and 2486 ng/mL (415), respectively. 13 Considering that the pharmacokinetics of venlafaxine XR and desvenlafaxine are linear and dose proportional up to 450 mg and 600 mg per day, respectively, one would expect equivalent doses of venlafaxine XR and desvenlafaxine to deliver similar amounts of total active drug (venlafaxine + desvenlafaxine) to systemic circulation. 2 , 6 Therefore, it may be unexpected to some that the FDA recommended daily target dose of desvenlafaxine is 50 mg since venlafaxine XR has demonstrated safety and efficacy up to 225 mg per day.

Clinical Trial Results

Despite pharmacokinetic similarities, clinical trial results are of primary importance when examining the safe and effective dosing range of desvenlafaxine. During development, Wyeth Pharmaceuticals sought approval for up to desvenlafaxine 200 mg daily, but the FDA selected 50 mg daily as the recommended dose. 10 Even though results from at least one of four 8-week double-blind, randomized, controlled clinical trials (Table 1) show statistically greater reductions in mean HAM-D17 total scores from baseline versus placebo for each desvenlafaxine dose studied (50 mg, 100 mg, 200 mg, 400 mg), the FDA rationalized that doses higher than 50 mg per day resulted in higher rates of side effects and discontinuations without any additional benefit. 17 , 24–27 Based on this rationale, it is unclear why the 100 mg tablet was also approved. Medications only need to achieve statistical separation from placebo in primary outcome (e.g., mean reduction of HAM-D17 score from baseline) to gain FDA-approval for the treatment of MDD, but depression response and remission rates should also be considered to judge a medication's clinically meaningful outcomes. Response and remission rates are inconsistent among doses in these four short-term trials, and it's possible that there are clinically meaningful differences between 50 mg and higher daily dosages.

Efficacy Results for 8-week, randomized, double blind, placebo controlled trials


What are the sexual side effects of antidepressants?

For many, taking antidepressants means experiencing some form of sexual dysfunction.

Experts are still researching the sexual side effects caused by antidepressants to figure out why they happen and how to prevent them. There may be some antidepressants that cause fewer sexual side effects, and there are also promising ways to manage or prevent these effects.

Share on Pinterest The sexual side effects from taking antidepressants will vary from person to person and will be different for men and women.

Taking antidepressant drugs can cause a wide range of side effects. Everything from gut issues to anxiety have been reported by people who take antidepressants.

Until recently, the sexual side effects caused by antidepressants were not often discussed with patients before prescribing the medications.

The symptoms of sexual dysfunction caused by taking antidepressants were highlighted in a recent study posted to Drug, Healthcare and Patient Safety.

Commonly reported symptoms include:

  • decreased sexual desire
  • loss of sexual excitement
  • diminished or delayed orgasm
  • loss of sensation
  • persistent genital arousal

These symptoms can change from person to person. There are also some symptoms that are particular to men and women. In men, more specific symptoms may occur, such as trouble getting or keeping an erection, or a persistent and painful erection. Men may also experience delayed or painful ejaculation.

Specific symptoms of sexual dysfunction caused by antidepressants in women include lactation that is not due to pregnancy or breastfeeding, and numbness in the vagina and nipples.

The symptoms of sexual dysfunction can impact a person’s quality of life. This can affect relationships, decrease self-esteem, and lead some people to stop taking their medication in order to find relief from the symptoms.

However, stopping taking medication abruptly can lead to withdrawal symptoms so this is not recommended. People who are experiencing sexual side effects could try some management techniques instead.

The reason that antidepressants cause sexual side effects is not fully understood. Depression itself can cause sexual side effects as well, so it can be difficult to understand which symptoms are caused by the disorder and which are caused by the medicine.

The side effects may also be due to the fact that each drug acts in a slightly different way in the body. For instance, selective serotonin reuptake inhibitors (SSRIs) work to increase the amount of serotonin circulating in the brain.

Serotonin helps the user feel less depressed and anxious, but too much serotonin may inhibit a person’s sex drive and make it harder to experience sexual pleasure.

Another theory is that as serotonin is increased, the levels of dopamine are decreased. This would be significant because dopamine is a chemical in the body that people need to feel stimulated. With less dopamine in the body, a person may have a hard time feeling sexually aroused.

Each antidepressant medication acts differently in the body. All of the main types of antidepressant have been linked to sexual side effects. The prevalence varies by the study and specific medication, however.

SSRIs

While there are many people who have sexual dysfunctions when taking all types of antidepressants, it is most commonly reported with SSRIs. Brand names include Zoloft, Prozac, and Paxil, among others.

A report in Drug, Healthcare and Patient Safety indicates that 58 to 70 percent of people who take SSRIs experience sexual side effects.

Tricyclic antidepressants (TCAs)

TCAs such as amitriptyline may be a better option for many patients. Amitriptyline was linked to sexual side effects in an estimated 7.7 to 10 percent of depressed people.

It seems that TCAs are a much better option than SSRIs for people with sexual dysfunctions caused by antidepressant drugs.

5-HT2 blockers

According to the report in Drug, Healthcare and Patient Safety, people who took newer 5-HT2 blockers experienced less symptoms of sexual dysfunction than those who took SSRIs.

For example, 8 percent of people taking the drug nefazodone experienced sexual side effects, while the drug mirtazapine produced sexual side effects in 24 percent of its cases. These figures are quite a lot lower than those reported with SSRIs.

People who are interested in switching medications should talk to their doctors for full details.

Monoamine oxidase inhibitors (MAOIs)

According to a journal posted in South African Family Practice, certain MAOIs have been associated with sexual side effects. This number does depend on the type of MAOI itself.

For instance, the drug phenelzine was associated with sexual dysfunction in up to 40 percent of cases.

Reversible inhibitor or monoamine oxidase A (RIMA)

When looking to avoid sexual side effects while taking antidepressants, many users turn to the RIMA drug moclobemide. Its brand names include Aurorix, Amira, and others.

Moclobemide appears to have a much lower incidence of sexual side effects. Less than 4 percent of moclobemide users reported sexual side effects while taking the drug. The drug is common in Australia and Finland, but is not approved for use in the United States.

Sexual dysfunction does not have to be a permanent side effect of taking antidepressants. In some cases, patients experience these symptoms within the first few weeks or months of taking their prescription, and then the symptoms become less severe.

Many people on antidepressants may also find success through managing their sexual side effects in one or more ways.

Switching medication

If the side effects caused by antidepressants are severe or very persistent, it may be possible to switch medications to try out results on another medication.

Working with their doctor, an individual will gradually come off their current medication and move to a new one. After a suitable trial period, the doctor may evaluate the person to see whether to change the dosage of the medication.

Lowering dosage

The dosage of the medication may also have an effect on the sexual side effects the patient experiences. If a patient feels their dosage is too high, they can have it evaluated by their doctor.

The doctor will begin putting the patient on lower doses of the drug. They will then monitor their progress to determine the lowest dose of the drug the person can take for it to be effective. Dosage is a very individual thing, and should not be adjusted without guidance from a doctor.

Personal changes

There are also ways to raise the libido without adjusting medications.

For many people, it is the will to have sex that is most affected by antidepressant medications. They may be physically able to be aroused, yet lack the willpower to carry out the act.

In these cases, it may be helpful to allow the body to go through the motions that usually make the person feel sexually aroused. Engaging in foreplay can stimulate the body and may help to influence the mind and increase the libido naturally.

Doctors may also recommend that people who take their medication on a daily basis, engage in sexual activity before taking their medication. In some cases, adding a sexual stimulant drug may help improve sex drive. As always, people should discuss these options with a doctor.

Because antidepressants may also decrease the amount of dopamine in the body, it is important for people taking them to boost their natural levels of dopamine. This can be as simple as getting plenty of rest and exercise, while also reducing stress levels.

Outlook

Many of the antidepressants on the market are linked to sexual side effects. The symptoms vary from person to person, but can greatly affect an individual’s life.

Managing these side effects can require a mixture of lifestyle changes, different medication, and dosage corrections. Working directly with a doctor, patients can help to reduce or eliminate sexual side effects caused by antidepressants.


ASSESSMENT OF PATIENTS WITH SEXUAL DYSFUNCTIONS

Evaluation of any patient with sexual dysfunction requires thorough understanding about the type of sexual dysfunction, factors associated with or contributing to sexual dysfunction and factors maintaining the sexual dysfunction. Accordingly, proper evaluation includes detailed history taking (sexual, medical and psychosocial), focused physical examination, laboratory tests (routine and specific) and consultation with appropriate specialists. Careful attention always be paid to the presence of significance comorbidities or underlying etiologies (e.g., cardiovascular disease, diabetes, depression).

Important aspects of evaluation of patients with sexual dysfunctions

Discussing sex-related issues can be embarrassing both for the clinician and the patient. Patients often carry the feeling of failure or that they are abnormal. Clinicians should anticipate the embarrassment of patient and acknowledge that it could be difficult talking about such issues. For example, the clinician may say, “Most people find it difficult to talk about these things and may feel a bit embarrassed. I𠆝 just like to reassure you that everything you say is confidential and that I𠆝 like to help you if I can. The first step is to find out exactly what's going on so that we can figure out how to make things right again. Please feel free to be open with me and to ask questions whenever you have any doubt.” Some of the other important issues for evaluation are given in Table-3 .

Table 3

Important aspects in evaluation of sexual dysfunctions

The basic principles of sexual history taking are given in table-4 . The patient needs to be asked to describe their problem in terms of time and manner of onset, its course over the period, its current status, and associated medical or psychological problems. While taking history, attention must be given to features which can help in distinguishing predominantly psychogenic from predominantly organic sexual dysfunctions ( Table-5 ). But, it is important to note that, in many cases, organic and psychogenic factors may coexist, particularly in individuals or couples with long-standing or chronic sexual dysfunction. In such cases, clinicians need to assess the independent and interactive role of both organic and psychogenic factors.

Table 4

History taking for sexual disorders

Table 5

Differentiating features between psychogenic and organic sexual dysfunction

An important aspect of sexual history taking in females is to remember that women play different roles at different times in their life. Many women have several roles-the professional or worker, housewife, mother, daughter, friend, and lover. It is often seen that the over the years as the demands of other roles increase, lover role fades away. Paying attention to these issues can be very useful, and this information can be collected by using a process called the “timetable of life.” Both partners can be asked to fill in a timetable representing a typical week from their initial interaction to the time of presentation. Various aspects which can be covered during the assessment of a week during a typical time frame may include, family time (that is, with children and partners), work time (both at work and work in the house), extended family time (with parents and relations), social time, personal time, and relationship time (time spent together as a couple). The relationship time must also include information about the sexual activity. A timetable almost always brings forward various elements missing in the relationship and personal time. Repeating the “timetable” for different times in life and comparing it during courtship, when sexual desire was probably good, with the timetable for a time when sexual desire was low is useful and can show how priorities change and how this influences desire for sexual activity. Looking at what happens in a sexual situation often gives much information about the defenses used when a patient engages in sexual activity. Clinician may also note what turns a patient on and off, how engorged he/she becomes in the sexual experience, and whether loss of desire occurs every time or it is situational. Other important aspects which can enhance the understanding about the problem include sexual fantasy, masturbation, genital functioning, and contraception.

Psychosocial history: Psychological factors associated with sexual dysfunction can be divided into three categories: predisposing factors, precipitating factors, and maintaining factors (See table-6 ), which can co-exist with each other. The areas to be explored in psychosocial history are enlisted in table-7 . It is to be remembered that the existence of an organic disease does not rule out the possibility of a coexisting psychogenic factor. Conversely, the presence of psychogenic conditions, such as anxiety, anger, guilt, or marital discord, need not be considered as evidence for a sole primary causation.

Table 6

Psychological factors associated with sexual dysfunctions

Table 7

Psychosocial assessment of sexual dysfunctions

The current psychological state need to be assessed with special focus on symptoms of anxiety or depression, low self-esteem and coping skills, previous and current partner relationships, history of sexual trauma/abuse, occupational and social stresses, socioeconomic status, and educational level. Sexual dysfunction may affect the patient's self-esteem and coping ability, as well as his or her social relationships and occupational performance. These aspects need to be assessed in each case. Clinicians need not assume that every patient is involved in a monogamous, heterosexual relationship.

Considering the fact that sexual problems arise in the interpersonal context, the clinician need to carefully assess past and present partner relationships. Another important aspect of psychosexual history is inquiring specifically about the quality of the relationship between the couple with respect to nonsexual factors, i.e., how to they get along on most issues, communication patterns, gender equality/inequality, level of commitment, dealing with stress, etc. While interviewing the couple together it is important to note the dynamics between the partners. Relationship problems may be due to intrinsic differences between the two, and expectations about sexual fulfillment may also vary. Many a times, lack of proper communication between the couple, which may be due to embarrassment, may be mistaken as lack of caring.

Another important aspect of psychosocial evaluation is the identification of patient/couple needs, expectations from each other, priorities and treatment preferences. These may be significantly influenced by cultural, social, ethnic and religious perspectives. Patient education about the problem is also important in enhancing therapeutic relationship, communication between patient and physician and ensuring patient compliance. Partner involvement is important. On the first visit, it is not always possible to involve the partner but efforts need to be made to involve the patient's partner early in the treatment process at the earliest. If the psychosocial assessment reveals the presence of significant psychological distress or conflict between the couple, further evaluation and management may be carried out either prior to, or along with treatment of sexual dysfunction.

Medical history: Historical events related to the presence of chronic disease, use of pharmacological agents, endocrine disorders, prior surgeries and trauma is to be carefully evaluated. While evaluating women careful medical history is to be obtained about any health problem that might affect sexual anatomy, the vascular system, the neurological system, and the endocrine system. Indirect causes i.e., factors that cause chronic pain, fatigue, and malaise may also contribute to dyspareunia.

Substance use History: Excessive use of alcohol or use of other recreational drugs may cause sexual dysfunction, either by a direct effect on the penile neurovascular system or by causing increased secretion of prolactin, reduction in production of testosterone, or both.

Treatment/Medication History: Clinicians should also enquire about the medication intake, including prescription drugs, over the counter medications and culturally sanctioned aphrodisiacs. Medications commonly associated with sexual dysfunction include diuretics (thiazides, spironolactone), sympatholytics agents (Central agents like methyldopa, clonidine and peripheral agents like reserpine), alpha blockers, beta blockers (particularly nonselective agents), angiotensin-converting enzyme inhibitors, calcium channel blockers, antipsychotics, antidepressants, benzodiazepines, buspirone, lithium, disulfiram, digoxin, histamine H2-receptor blockers, ketoconazole, niacin, phenobarbital, phenytoin, allopurinol, gemfibrozil, clofiberate, phenobarbital, phenytoin, danazol, GnRH agonists, oral contraceptives etc.

Physical Examination

Every effort be made to ensure the privacy, confidentiality and personal comfort of the patient while conducting the physical examination. Careful physical examination not only corroborates the medical history but at times also reveals unsuspected physical findings (e.g., decreased peripheral pulses, vaginal atrophy, atrophic testes, penile plaque).

In addition, to the general and systemic evaluations, detailed assessment of gonadal function, vascular competence, neurological integrity, and genital organ normalcy is to be performed on every patient. Patients suspected of hypogonadism need to be assessed for evidence of muscle development, size and structure of the penis, normal urethral opening, hypospadias, size and consistency of the testes and the prostate. Alcohol swabs can be used to test penile temperature sensation. Bulbo-cavernosus reflex can be elicited by squeezing the glans penis and assessing the evoked contractions of external anal sphincter or bulbo-cavernosus muscles. This reflex response is clinically detectable in 70% of normal males. The penis also needs to be examined for evidence of any masses or plaque formation, angulation, unprovoked persistent erection, or tight unretractable foreskin.

Similarly in females genital examination is often highly informative, especially in cases of dyspareunia, vaginismus, with a history of pelvic trauma and with any disease potentially affecting genital health. If there are indications from history, the opportunity for pap smear/sexually transmitted disease investigation is to be taken.

Recommended Laboratory Testing

Recommended laboratory tests for men and women with sexual problems typically include blood glucose levels, cholesterol, lipids, hormonal profile and X-ray spine for spina bifida. Additional laboratory tests (e.g., thyroid function) may be performed at the discretion of the clinician, based on the medical history and clinician's judgment. When an infective etiology for dyspareunia remains a possibility- vaginal, cervical and vulval discharge microscopy/cultures need to be performed.

Assessment of Knowledge and Attitude towards sex

Few patients may not actually have sexual dysfunction, but may perceive the same, because of poor knowledge and negativistic attitude towards sex. Further, in some patients the sexual problems may be attributed to the beliefs and cultural practices. Some of the scales like Sexual Knowledge and Attitude Questionnaire and Dhat syndrome Questionnaire, which have been validated in the Indian context, may be used for structured assessment and documentation. These scales can also help in determining the area to be focused in sex education and psychoeducation.

Specialist Consultation and Referral

Patients with history of medical problems be referred to appropriate specialty to evaluate the severity and state of disease control (See table-8 ). Sometimes there may not be a need for referral, but if patient requests for the same, it is to be done. Further diagnostic evaluation also needs to be conducted in case of lifelong or primary sexual dysfunction, in the presence of specific anatomic or endocrine factors and failure of initial therapy. Patients with hyposexual desire and absent or retarded emission or anorgasmia may need to be evaluated for the presence of diseases involving the nervous system. Patients with prolonged or painful erection need to be evaluated for the possibility of primary penile disease, hematological disorder, or other systemic diseases associated with penile complication.

Table 8

Medical history, physical examination and investigations for sexual dysfunctions

By the end of assessment the clinician should be able to answer the following questions for themselves to plan management:

Does patient/couple actually have sexual dysfunction?

Whether the dysfunction is primarily psychogenic or primarily organic?

If the dysfunction has organic etiology, then is there a psychological overlay too?

If there are more than one dysfunction, then which is the primary?

Does patient has any comorbid psychiatric disorder?

If subject has a psychiatric disorder, then is the sexual dysfunction secondary to it?

If subject has a psychiatric disorder, then how severe it is?

Is there a marital discord between the couple, which needs to be addressed?

What is the motivation of the patient/couple to seek treatment?

What is the level of psychological sophistication?


Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors

To evaluate the possible influence of buspirone on sexual dysfunction in depressed patients treated with a selective serotonin reuptake inhibitor (SSRI), we analyzed data from a placebo-controlled trial designed to explore the efficacy of buspirone as add-on treatment for patients not responding to an SSRI alone. At baseline, all patients met the criteria for a major depressive episode according to DSM-IV and had received citalopram or paroxetine during a minimum of 4 weeks without responding to the treatment. Buspirone (flexible dosage, 20-60 mg/day) or placebo was added to the SSRI for 4 weeks the mean daily dose of buspirone at endpoint was 48.5 mg (SD = 1.0). Sexual dysfunction was evaluated using a structured interview. Before starting medication with buspirone or placebo, 40% (47 of 117) reported at least one kind of sexual dysfunction (decreased libido, ejaculatory dysfunction, orgasmic dysfunction). During the 4 weeks of treatment, approximately 58% of subjects treated with buspirone reported an improvement with respect to sexual function in the placebo group, the response rate was 30%. The difference between placebo and active drug treatment was more pronounced in women than in men. The response was obvious during the first week, with no further improvement during the course of the study. It is suggested that the effect of buspirone on sexual dysfunction is a result of a reversal of SSRI-induced sexual side effects rather than of an antidepressant effect of the drug.


Discussion

Patient education on the sexual side-effect profiles of SSRIs is critical to medication adherence, resolution of depressive symptoms, and improving quality of life. Delaying this discussion may result in confusion and distrust of pharmacotherapies and health care providers, making it more difficult to adjust and recommend medications later on. This literature review serves as an aid to better facilitate patient education and treatment. However, as with all narrative studies, flaws of this study include potential for selection bias as one reviewer was responsible for article selection. Additionally, given the wide breadth of articles analyzed, there may be some concerns with external validity because subject groups were heterogeneous. Lastly, antidepressants include a wide range of pharmacotherapy and nonpharmacotherapy options and not every facet was explored, potentially contributing to external bias.


Mental illness and sexual dysfunction

There is little in the literature specifically on older people's mental illness and sexuality however, the impact of mental illness on sexuality and sexual functioning is wide and well-studied. It has been estimated that only 44.9% of individuals with a severe mental illness were sexually active in the past 3 months, and perceptions of stigma and poor self-esteem are important mediators in the reduction of sexual activity (Bonfils Reference Bonfils, Firmin and Salyers 2015).

Depression and anxiety

Sexual dysfunction is strongly associated with depression and is related to several depressive symptoms, such as low energy, low motivation, poor self-esteem, anhedonia and reduced libido. As already discussed, this is compounded by many antidepressants conferring a risk of sexual side-effects. It has been suggested that the prevalence of sexual dysfunction in people with depression is twice that in healthy controls and that recurrent depression may be more associated with sexual dysfunction than single episodes of depression (Montejo Reference Montejo, Montejo and Baldwin 2018). A study that attempted to identify the baseline of sexual dysfunction in depressed individuals before treatment found that around one-third reported reduced interest in sex, with the most common dysfunction being reduced levels of arousal, followed by problems achieving orgasm or ejaculation (Thakurta Reference Thakurta, Singh and Bhattacharya 2012).

The burden of sexual dysfunction appears to be higher in major depressive illness (76%) than in the common anxiety disorders, although there are still significant rates of sexual dysfunction reported in conditions such as obsessive–compulsive disorder (OCD) (50%) and generalised anxiety disorder (64%), with low desire being the most common dysfunction (Kendurkar Reference Kendurkar and Kaur 2008). Fear of contamination during sexual activity is thought to be an important aspect of sexual dysfunction in OCD (Sabetnejad Reference Sabetnejad, Assarian and Omidi 2016). Reduced sexual functioning, however, can still be found in people with OCD irrespective of fears of contamination or medication use (Vulink Reference Vulink, Denys and Bus 2006).

A randomised controlled trial looked at response of sexual dysfunction in women with OCD to treatment with fluoxetine or cognitive–behavioural therapy (CBT) and found that those who received CBT showed significant improvement in areas of desire, arousal and orgasm though not in problems of reduced lubrication and dyspareunia (Sabetnejad Reference Sabetnejad, Assarian and Omidi 2016). There was a reported reduction in satisfaction and sexual function in the group treated with fluoxetine, possibly related to sexual side-effects (Sabetnejad Reference Sabetnejad, Assarian and Omidi 2016). The use of CBT more generally to target sexual dysfunction is an area where there is currently a lack of strong evidence to support formulation of guidelines (ter Kuile Reference ter Kuile, Both and van Lankveld 2010). Both OCD and panic disorders are seen to be related to sexual dysfunction independent of medication use therefore assessment of sexual functioning before psychotropic initiation could be an important aspect of treatment and prevention of further difficulties (Aksoy Reference Aksoy, Aksoy and Maner 2012).

Eating disorders

Sexual dysfunctions are commonly seen in eating disorders and the psychopathology of these disorders is thought to be an important factor in perpetuating these problems (Castellini Reference Castellini, Lo Sauro and Lelli 2013). The dysfunctions are likely to be multifactorial, including contribution from physiological changes related to low body weight and starvation (e.g. lethargy, amenorrhoea), comorbid depressive symptoms, problems with self-esteem and perceived body image (Castellini Reference Castellini, Lelli and Lo Sauro 2012). There is suggestion that the mechanisms of sexual dysfunction may vary between anorexia nervosa and bulimia nervosa: in one study, dysfunction was found to correlate with body mass index in anorexia, whereas the correlation found in bulimia was with depressive symptoms measured by the Beck Depression Inventory (Gonidakis Reference Gonidakis, Kravvariti and Varsou 2015).

Although treatment of sexual dysfunction in the eating disorder population has not been studied in detail it is thought that treatment focusing on body image, binge eating and emotional eating could improve sexual function (Castellini Reference Castellini, Lelli and Lo Sauro 2012). Psychotropic treatment of the eating disorder and any comorbid depressive illness would also appear to be a sensible approach to improving underlying dysfunctions, keeping in mind the difficulty with sexual side-effects.

Schizophrenia

Sexual dysfunction in schizophrenia is complex (Box 1): it can be related to symptoms of the condition (particularly negative symptoms), antipsychotic medication, comorbid physical health conditions, stigma and other psychosocial factors (de Boer Reference de Boer, Castelein and Wiersma 2015). A study of drug-free men with psychosis in India showed a prevalence of 25% for sexual dysfunction in those engaged in sexual activity dysfunction was related to both older age and later age at illness onset (Ravichandran Reference Ravichandran, Gopalakrishnan and Kuruvilla 2019). Other studies have suggested prevalence of dysfunction between 30 and 60% in drug-free patients with psychosis and prevalence as high as 80% in a more general population of men with schizophrenia (Ravichandran Reference Ravichandran, Gopalakrishnan and Kuruvilla 2019). In a rural Chinese population with schizophrenia 71.3% reported sexual dysfunction and this was associated again with old age and with burden of negative symptoms (Huang Reference Huang, Hou and Ng 2019). Although there is a paucity of research into this area it has also been suggested that loss of interest in sex in people with schizophrenia is associated with advancing age, female gender, cardiovascular medication, negative symptoms and lower sexual self-efficacy (self-confidence and self-control in sexual experiences) (Bianco Reference Bianco, Pratt and Ferron 2019). It is not clear whether treatment of the psychotic disorder confers an improvement in dysfunctions: a study of men with schizophrenia in remission still showed high levels of dysfunction (between 78.4 and 97.1%) across five domains of sexual functioning (Kheng Yee Reference Kheng Yee, Muhd Ramli and Che Ismail 2014). Another aspect of sexuality studied in schizophrenia is risky sexual behaviour, which refers to unprotected sex with risk of unwanted/unintended pregnancy and transmission of sexual diseases. A prevalence of 39.4% was reported in a study of 429 people with schizophrenia in Ethiopia, with associated factors including male gender, younger age, positive symptoms and substance misuse (Negash Reference Negash, Asmamewu and Alemu 2019).

BOX 1 Case vignette 1: antipsychotic treatment for sexualised behaviour in paranoid schizophrenia

A 78-year-old man with paranoid schizophrenia was admitted to hospital showing signs of mental disorder, including hallucinations, religious delusions, delusions of influence and paranoid delusions. He was displaying suspicious, hostile, aggressive and sexualised behaviour. He had falsely accused his daughter of incest, saying that she wanted to marry him. On the ward, he follows a female in-patient, wanting to tell her that he ‘does not have sperm anymore and wouldn't have children’. He tells doctors that he is concerned that he is not having erections, is sexually inactive and would like to be back to normal again. He has been masturbating every night but could not get any result.

A computed tomography (CT) head scan shows mild ischaemia and mild cerebral volume loss without lobar predominance. He scores 69/100 on the Addenbrooke's Cognitive Examination-III (ACE-III). There is no evidence of frontotemporal dementia.

With proper antipsychotic treatment his symptoms subsided and he was discharged from hospital back into the community.

Bipolar affective disorder

Bipolar affective disorder can be associated with both hyposexual disorders and hypersexuality, often related to the polarity of the current episode of the illness. Sexual dysfunction during bipolar depression can be thought of as similar to the dysfunction seen in a unipolar depressive illness, and as in that illness there are also reports of residual sexual dysfunction in euthymic patients (Montejo Reference Montejo, Montejo and Baldwin 2018). Residual sexual dysfunction has been shown to affect medication adherence in clinically stable individuals with bipolar disorder so is important to keep in mind when assessing the patient (Grover Reference Grover, Ghosh and Sarkar 2014). Sexual distress and dissatisfaction have been found to be higher in people with bipolar disorder than in the general population and higher rates of sexual desire are seen in these patients in comparison with those with unipolar depression (Sørensen Reference Sørensen, Giraldi and Vinberg 2017). Stigma again appears to play an important role in bipolar disorder: a US study found that rates of marriage were lower in adults with bipolar disorder (32.8%) than in the general population (55.7%), and 52.9% of patients felt that stigma affected their relationship success (Jackson Reference Jackson, Kolikonda and Yeruva 2018). Mania-induced hypersexuality and risky sexual behaviour is well-known but understudied in this population, as are lower intensity increases in sexual behaviour and the impact of cycling mood on relationships (Kopeykina Reference Kopeykina, Kim and Khatun 2016). Guidelines for treating acute manic episodes are well established but again there is little specific guidance on hypersexuality and the recurring problems of sexual side-effects of medication.



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