Can SSRI make things worse in the long term or cause delayed depression?

Can SSRI make things worse in the long term or cause delayed depression?

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I found two articles that mention that taking SSRI for depression can actually make the depression worse.

  • "Now Antidepressant-Induced Chronic Depression Has a Name: Tardive Dysphoria" on Psychology Today.
  • "Antidepressants Make Things Worse in the Long Term" on the Behaviorism and Mental Health blog.

Is this true? Can Tardive Dysphoria (delayed depression) be caused by SSRI?

They seem pretty convincing and I can't find anything against it but if it's true, it basically means that depression treatment is going back to the 60's before SSRI were invented.

Contrary to another post here, in my opinion and also that of an increasing majority of researchers studying this field, SSRIs and the so called 'antidepressant' drugs cause great harm.

Firstly here is a list of common side effects: Insomnia (which is common in depression anyway), increased anxiousness, feeling sick, indigestion, diarrhea or constipation, loss of appetite, fluctuations in weight, dizziness, blurred vision, dry mouth, excessive sweating, headaches, reduced sex drive, difficulty achieving orgasm, erectile dysfunction.

None of these are good effects which is why we don't give them to people who are 'healthy'. More importantly the devastating effect these side effects can have on a patients life could potentially be far more harmful than before the drug was taken, for example increased marital problems. According to Joanna Moncrieff these effects compound depression, and more importantly disturb the chemical balance in the the brain, and as a result compound or cause the very symptoms they are meant to cure. Central to this notion and the question presented here, the long-term use of SSRIs may causes what we call 'serotonin induced apathy', in other words, after initial positive effect of SSRIs (quiet possibly short-term placebo effect), patients become indifferent to their environments. Furthermore Long-term use of SSRIs leads to abnormal brain neurogenesis not seen in non-depressed samples, this is often taken to as proof of how SSRIs exert there action, or rather it was before 2008 (see below meta analysis). However it seems that this neurogenesis is less likely to be positive considering the negative effects and lack of efficacy SSRIs display.

The long-term use of SSRIs often leads to the development of apathy, which utimatley will lead many patients back into depression. The rate of relapse in people taking 'anti-depressants' is >40% while patients with placebo is roughly 24%. If that isn't bad enough at a 12 month follow up only <5% of patients are in remission for their depression. Why might this be? Well a 2008 meta-analysis by Kirsch et al found that all 'anti-depressants' are below clinical levels of acceptance, in other words no more effective than placebo. However it should be noted that in severe depression SSRIs are useful only!

The reason anti-depressants such as SSRIs are ineffective is because of the simplistic approach taken to treatment with these drugs. The brain is not some 'big bag of chemicals', neurons are not purely serotonergic in fact they often release multiple NTs. And crucially serotonin NT is used throughout the central nervous system, for more than mood regulation. The fact that SSRIs do not work over the long-term tells us the serotonin theory of depression is wrong. Perhaps more importantly roughly 10% of people in the UK are on 'anti-depressants', we can talk about over medicalisation of mental health, but the reality is large amounts of people are taking these drugs for large amounts of time (9-12 months recommend). This is not helped by the fact that governments are more interested in investing in cheap medical 'cures' than long-term methods with greater efficacy that cost more.

Sorry its so long, and I'm sorry its so short there is so much to say about how SSRIs don't work and how bad they are regarding people thinking they are getting effective cures, along with the neuroscience and discussions on publication bias. Its a fascinating topic, thanks for the question.

In general no SSRIs lasts long enough as an effective treatment for most patients to cause long term harm. Most of the time people are only on them for weeks or months before many of their symptoms are reduced. If someone remains on antidepressants for long term treatment for something like OCD intrusive thoughts or major depression it is possibility for the medicine to harm the nervous system. This is unlikely though because SSRIs are not that effective and most of the time they have to cycled to another kind of medicine for most diseases as the diseases adapt to the medication. The meds stop working and the doctor and patient must switch to another type.

Yes Tardive Dysphoria does really happen and its happened to me but no its not a big deal nor is it life altering. No we are not going back to the 60s. As there are other options in treatments. Doctors have known that inappropriate dosages or incorrect medications do cause depression. Sometimes more of the same SSRI will fix the problem. The antipsychotics and antidepressants have long since been known to sometimes have inverse effects on some patients. This is the reason why abilify though it be the latest and greatest antipsychotic is not necessarily the medicine of choice because of it high probability to induce psychosis. Thats because there are 8 genes responsible for the schizo type psychosis and how each person responds to medication varies based on their gene and biology. Likewise also for depression a much less understood condition the person's biology is going to determine their response to medication and final treatment.

CEP survey report shows that antidepressant withdrawal can devastate lives

The following is taken from the conclusion of a CEP survey report published today on behalf of the All Party Parliamentary Group for Prescribed Drug Dependence entitled: ‘ Antidepressant Withdrawal: A Survey of Patients’ Experience’:

“The responses to this survey make clear the ruinous impact of antidepressant withdrawal on some individuals, as well as the failure of those responsible for their care to understand and to treat the problem. It also reveals that other government-funded sources of support are entirely inadequate, with individuals left to fend for themselves or rely on internet-based support groups.

Survey respondents describe the suffering caused by withdrawal in the most severe terms, with some claiming that the process had devastated or ruined their lives. For many the experience lasts more than one year, with some respondents describing incapacitating symptoms for longer than five years, which can lead to the breakdown of marriages, careers and – for over 25% of respondents – indefinite disability.

Respondents to this survey say that their doctors or psychiatrists mostly did not inform them about the risks of withdrawal, which could be considered a failure of informed consent. Many believe they were told to withdraw or taper too quickly, which they reported aggravated their symptoms. Furthermore, some say that doctors and psychiatrists subsequently denied that these symptoms were caused by withdrawal, and misdiagnosed withdrawal as relapse or as a new disorder, sometimes proposing new medication. It is not surprising that for some patients this leads to a profound distrust of the medical profession.

Respondents also make clear that other sources of support, such as NHS Choices, NHS 111 and traditional drug & alcohol treatment services, are similarly uniformed and unhelpful. This leads many to rely entirely on online peer support services, such as

This survey provides compelling evidence that antidepressant withdrawal can have devastating, life-changing consequences for some individuals. Doctors, psychiatrists and other medical professionals must urgently be provided with appropriate training in this area, both at medical school and as part of their continuing professional development. Clinical guidelines must also be updated to reflect the actual incidence, severity and duration of antidepressant withdrawal, and to enable doctors, psychiatrists and other practitioners to provide appropriate care, including slow tapering protocols. Lastly, government must ensure that individuals affected by withdrawal have access to proper support services, which we recommend should include local support groups as well as a national 24 hour helpline and accompanying website.”

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39 Responses to CEP survey report shows that antidepressant withdrawal can devastate lives

It’s not just withdrawal it’s the damage side effects and contraindications cause. For 20 years I was prescribed Amitriptyline not as an antidepressant but as a muscle relaxant and while recently in hospital to be assessed for stents the Cardiologist asked everyone in the theatre to leave ‘To save my embarrassment’ When they left he asked if I was a HEROIN addict’ I had to laugh because I couldn’t believe what he was asking. I asked why he thought that and he said ‘I’ve been a consultant for decades and have seen the damage to your heart in all heroin addicts’ I had no response to that and he proceeded to complete the process. When I arrived home I did some research into the medications I was taking and discovered that one of the main effects of this egregious drug is that it damages the heart and the manufacturers themselves say it shouldn’t be taken for more than 9 months at a time for that reason. I spoke to my GP and asked why in all the years he’d prescribed this drug he hadn’t told me of the dangers. He said ‘It didn’t occur to me till you mentioned it’ More recently and triple stents later I was at the GP and saw a different doctor who was discussing antidepressants with me I told her that there were some I couldn’t take because they’d made me ill and was quite specific that Amitriptyline had damaged my heart to the extent my cardiologist thought I was a heroin addict. The first drug she offered literally minutes later was Amitriptyline I said no I was in absolute shock. She proceeded to offer me another antidepressant that was marked on a sheet in front of her as a drug I’d used to try to kill myself with in the 80’s – She’s fully aware as are many GP’s that this (One of many, many antidepressants on the market) are dangerous in their own right and whenever they’re removed for any reason they’re then marketed to treat other conditions. It’s not just antidepressants either the truth about the dangers of Statins. Big pharma is not in the business of curing people there’s no money in it. All they want is more customers

Well what can i say…WOW!!
I cant thank CEP enough for this.
This is the best piece of ‘truth’ telling i have read on this subject.

“Respondents to this survey say that their doctors or psychiatrists mostly did not inform them about the risks of withdrawal”

Its not mostly did not inform its ‘totally’ did not inform of its nature and extent because doctors dont even have the word ‘withdrawal ‘ in their medical dictionary or vocab.

The medical profession should be deeply ashamed at their tragic failure and harm induced on so many (millions).

Once again thankyou CEP for the tremendous work you are doing.

My thoughts too. I hope like nothing else this is made known all round the world to all these under the influence ass clowns who play down what these piece of shit drugs do to those who use it and who dismiss the grueling, relentlessness of the dark hole that is WITHDRAWAL (not that other rediculous term for it which i feel implies it’s our fault), and when they know the truth(if their grandeur allows their knob heads to accept it) i hope they.ll feel like the pieces of shit they are for dismissing the feedback of millions, preferring what.s given to them in convenient little handbooks. Watch them scurry to discredit a study based on real life experiences, real accounts and not a manipulated maximum profit study.

This is the sort of thing that should be on the front page of Britians newspapers.

Not some selfish self conscience thin skinned guilt induced resignation from some low life toe rag impervious to the evidence drug pusher psychiatrist with mountainous undisclosed conflicts of interest and with much blood on his hands.

As i read this this morning i am reminded of the statement by David Healy which i totally agree with being
“The ssri era will soon stand as one of the most shameful in the history of medicine.”

Personally i think its even worse and say it is THE biggest crime against humanity.

GSK should be litigated so hard that the company is bankrupted and shut down for good. GSK should be held liable for the costs of setting up withdrawal and tapering (we are talking safe tapering that is for many years NOT 2-3 weeks) clinics across the country.

Why do we need specific withdrawal and tapering clinics set up across the country?
Because ‘do not discontiunue your medications without consultation with a doctor’ is one of the most moronically stupid and stomach sickening dangerous things you can read.

Asking a doctor for taper advise is like asking a fish for instructions to walk though a field full of landmines.

As you can see i am very thrilled regarding this CEP posting. Especially at a time when i felt voices were not being heard maybe this time some traction will be made.

I am filled with mixed emotions.
By the way mixed emotions can be described as watching Wendy Burns, David Baldwin and Andrew Witty (counting their bottle tops they are accumulating in their bank accounts while) driving over a cliff in my brand new Holden.

Im happy. Happy because there is some validation for the millions harmed and betrayed.

Im angry. Angry because it has taken so long for the truth to come out and that the medical profession have continually done what they did when the thalidomide tragedy broke….and that is to deny deny deny. And we all thought that there couldnt possibly be another drug horror story. How wrong we were, the reality is frightening.

This is my last post…i promise.

Its seems ironic this study comes out today for this very week in NZ (8-14 oct 18) is mental health week.

Sadly this is all a hoodwinked and blind society can come up with as they try to understand the horror that is surfacing across the country. (i dont think NZ is the only country struggling to understand such problems). They think more money funnelled into MH and more recognition and doctor support of these people is what is needed. Even subjects at school are covering this unfortunate topic.

Yet the real reason for this disabling cognitive implosion by society is being missed…..
psychiatry and its rosey red apples are THE reason for this brain altering ruination of lives.

Lets not forget psychiatry has a dreadful history of harm…beatings, purges, chemical-induced convulsions, ECT, frontal labotomies etc….they have pushed an unvalidated DSM (in other words total BS) on people forcing them to adopt a debilitating internal narrative but even worse that narrative demands they swallow a drug from the doctor…….so now with ssris and the like they have really topped themselves in the harm department!

I loathe the words M.I. and M.H. wouldnt it be so much more empowering to call it psychological health week. And wouldnt it be far better to spend the week informing people of some of the most dangerous things they could ever do …like go and talk to a doctor regarding anything that an ssri could be prescribed for from a sore toe to a headache and anything inbetween.
Im sure the Troy Skinners of this world would agree with me.

Troy Skinner an iatrogenic victims …never been in trouble in his life, preparing to study law at university …now in jail!

I as a mother have been labeled ( in my sons notes) as having serious mental health issues. I have dared to stand up to drs, psychs and many other ‘health care professionals. All three of my adult children for very different reasons have been prescribed these toxins. One lost a three yr old with meningitis, the other for PND and finally one who HAD his own 4 bed house, new car and own business. At age 20 and only with a second opinion was diagnosed with Hodgkin’s disease. The chemotherapy was a trial drug witch disagreed with him. He was sectioned given radiotherapy plus many other psychotropic including Citalopram 60mg. More recently he was sectioned again, many falls and wheelchair bound. Again the blame and accusations including safeguarding issues were directed at me….in light of his history I asked for scans. These were refused. I got a private referral for this myself. It is almost 3am I am still up with him and need to give this next piece of information

My daughter managed to get him to a scan. One hour before the scan a senior registrar pointed at me in the ward he was on..” it’s you, you’re to blame putting it into his head he can’t walk!” This was reported to PALS immediately and is documented.

The scan revealed a 3 cm tumour between C5 – C6 ..emergency surgery followed. Neurosurgeon informed us it was 29 – 30 byears old..

There is so much more to this which I have fairly well documented…my sone needs care as do my other children…this is an incomplete story which must be told in full to help others.

The above incomplete comment ,should read after an 11 hour surgery which revealed a 20 -30 year tumour. K

Thank you to CEP and all the people who took time to give information regarding withdrawal and protracted withdrawal from these drugs. I took Escitalopram for 11 years after experiencing anxiety when going through the menopause. I tried to come off the drug a couple of times and had awful symptoms so I thought I needed the pills. I now know this was withdrawal. I tapered off quite slowly after having advice from a friend who had come off long term Benzodiazepines and had suffered terrible withdrawal. I started having symptoms just reducing the drug which were balance issues. I saw a Neurologist who said I had Sensory Ataxia and said my alcohol consumption was to blame. I was horrified as I hardly drank. Further into reducing the pills I started having mood swings and was very down. I couldn’t cope with things that previously hadn’t bothered me. After stopping the meds altogether I went downhill. I had gastric issues like diarrhoea and felt nauseous all the time. I lost over a stone in weight. I couldn’t get to sleep and if I did I would wake up with what I named the morning terrors. I felt weak and fatigued and couldn’t function. I couldn’t make decisions and every little issue was magnified 100 fold. I cried all the time and lost all interest in everything I’d previously loved. I couldn’t shop or cook and I was scared of everything. I couldn’t sit still and had an inner restlessness. I felt like I had no life and was even scared of being in my own home. It was so bad that I considered ending my life. I thought I was going mad. I had always been a worrier but I had never ever had anxiety and fear like this. My husband and family were very supportive but were at their wits end and all along all the Doctors I saw told me it couldn’t be withdrawal as it only last a few weeks. My IBS had gone haywire and I paid privately to see a Professor who was a Gastroenterologist. He confirmed it was coming off the tablets that was the cause and said it could last a couple of years. I was determined to stick it out but ended up seeing the Crisis Team when I became suicidal. I was seen by a Psychiatrist and told I was deluded about it being withdrawal and I had rebound depression. I was told you need the tablets like diabetics need insulin. You have a chemical imbalance. I ended up back on pills. I felt a failure. I had fought it tooth and nail but I couldn’t go on the way I was. Going back on the meds has taken some of the withdrawal away but I’m not sure if I’ll ever be the person I was. Things definitely need to change. I turned to the Internet for information and even rang Bristol and District Tranquilliser Project when I felt at my worst. There was nobody else to turn to and it felt awful not to be believed. Thank you again to CEP for all your hard work and for publishing these results.

Your story is very similar to mine. After several failed attempts I am back up to 20mg citalopram,the more severe withdrawals have stopped but I am a shadow of my former self and I am scared for what the future holds

Thank you so much for these reports and everything you do to expose the dangers of these evil drugs. Absolutely ruined my life. I’ve never known anything so horrific and mindbending as seroxat withdrawal. They should never have been released.

Thank you cepuk for this absolutely essential and long-overdue research and all you lovely people above for sharing. I hope that kiwi will not stop commenting – her anger is shared by me, and I am just the mother of a sufferer from poisoning by his GPs, with SSRIs, overlapped with Amitryptiline, then finally Mirtazipine to counter the psychotic episode and hypomania that resulted. While I was begging the Health Minister to stop these dangerous drugs being prescribed to stressed people, to set up NHS ashrams in their stead, and appealing to his GP to return our stolen son, and advising MHRA, who just returned my complaint attached to a Yelloow Card number – my son lost his home, his family, his work – and most of all – his brilliant mind. 2 years on he is still struggling in withdrawal and possibly PTSD from the awful court case he was put through – never having harmed anyone, but treated as a dangerous criminal. Wherever he has turned to for help, the outcome has been prescriptions for more and more medications. He may be brain-damaged, but he is not stupid and does not take these poisons pushed by the medical profession – ignorant and corrupt the majority of them. We have a minister for suicide prevention now – so any drugs that include suicide ideation on the PIL leaflet should be banned immediately.

I hear you on the banning but there is a problem with it too. Taking it away from millions will cause millions to be in wd from very quick tapers. Will have grim consequences for them. Don.t get me wrong though i know the pain all too well.

This has been picked up by the Scottish Herald The more we share this the chance there is we’ll be heard

Scotland’s secret addicts?: the patients hooked on antidepressants and harmed by withdrawal “It was a week after stopping antidepressants in 2011 when Alyne Duthie first began experiencing the symptoms which would ultimate drive her to try to end her life.”

Thank goodness for this report……at last. It describes the worst 10 months of my life withdrawing from 25 years of SSRIs and the experience has been life changing. Unbelievably, my GP still insists there is a “psychological element” to my symptoms. We need to shout loud and long about this. I am appalled that I was so ignorant about the medication I was taking for so long, but it is unforgivable that it is taking so long to reliably inform health professionals and treatment protocols.


In September 2007, a group of researchers made headlines when they reported a forty-fold increase in the number of office visits in which children had a diagnosis of bipolar disorder (BP)[1]. The researchers estimated that whereas, in 1994-1995, in about 25 out of every 100,000 visits a child had a bipolar diagnosis, the number increased to 1,003 per 100,000 by 2002-2003. During the same ten-year period, office visits by adults with a BP diagnosis almost doubled from 905 to 1,679 per 100,000 annually, suggesting that BP diagnoses reported by community-based clinicians have increased across the age span. But the very low base rate of this diagnosis in youth coupled with a rapid rise signaled a major practice change.

Once thought rare in pre-adolescents, BP is now increasingly diagnosed in children, including preschoolers [2]. The drugs used to treat it include mood stabilizers and antipsychotics [3], which carry the risk of significant side effects. Perhaps even more than the diagnosis and treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and childhood depression before it, the ascension of the BP diagnosis in children and its treatment with medications whose risk/benefit profiles are inadequately established have generated debate in both lay and professional communities.

This commentary grows out of a workshop that explored the debates regarding the increase of BP diagnoses in children under 17. The workshop was the third of five in a series aimed at exploring the controversies concerning the diagnosis and treatment of mood and behavioral disturbances in children the workshop was highly interdisciplinary, including child psychiatrists, psychologists, philosophers, sociologists, anthropologists, and others. Our first commentary, which grew out of our first workshop, explored the debates in general [4]. Our second commentary explained why informed people can disagree about ADHD diagnosis and treatment we explored the "zone of ambiguity" between those children who clearly do--and those who clearly do not--have ADHD and the complexities of identifying and implementing effective treatment [5]. In this commentary, we focus on the intense and complex debate among child psychiatrists and psychologists about how best to conceptualize the serious emotional and behavioral disturbances exhibited by the group of children currently receiving a BP diagnosis.

This series of workshops was funded by a National Institute of Mental Health (NIMH) grant to The Hastings Center, which is an independent, nonprofit, nonpartisan, bioethics research institute. The authors of this commentary are scholars at The Hastings Center. One of us has a background in philosophical bioethics (EP) and the other a background in law and bioethics (JJ). Because neither of us has training in psychiatry, we relied on the generous advice of child psychiatrist Dr. Benedetto Vitiello at NIMH and former NIMH director Dr. Steven Hyman, who helped us identify a wide range of views within child psychiatry and psychology. We also relied on the generous advice of anthropologist Dr. Sarah Harkness to help identify individuals who study how social and cultural context can affect the interpretation of children's emotions and behaviors. Almost without exception, the experts we invited to the workshop accepted, even though we were able to offer only a very modest honorarium. We held the workshop, consisting of presentations and lengthy follow-up conversations, in New York City on April 24-25, 2008. (For more on our method, see [4]). None of our advisors or workshop members, listed at the end of this commentary, bears any responsibility for its contents. This is not a consensus document.

Our primary aim in this commentary is to fairly describe the debates that occurred at the workshop. As part of our effort to be as accurate as possible, we will sometimes include workshop participants' exact words. Based on our analysis of the presentations and discussion at the workshop, as well as our reading in the professional literature, we conclude that the proposed new diagnosis of SMD, on which the Diagnostic and Statistical Manual (DSM) V's proposed diagnosis of Temper Dysregulation Disorder with Dysphoria (TDD) is based, may help to clarify the debate about a troubled group of children who are currently receiving a BP diagnosis but do not neatly fit DSM IV criteria. We will suggest that, though in the US a BP diagnosis can get children the treatment, school accommodations, and insurance reimbursements they desperately need and deserve, if applied too widely it can do more harm than good.

Disagreement about labels, but agreement that these children desperately need help

Some researchers, physicians, and parents argue that the sharp increase in rates of BP diagnosis simply reflects overdue recognition of this disorder in children. As workshop participant and patient advocate Susan Resko urged us to remember, a 40-fold increase sounds like a lot until one recalls the raw percentages: from the BP diagnosis being present in 0.025% of office visits in 1994 to it being present in approximately 1.0% of the visits in 2003. Moreover, these percentages refer to a clinic sample, not the community at large.

Those who are not alarmed by the increase suggest that in the past clinicians missed cases of BP because they did not understand that it can affect children and because BP symptoms can look different in children and adults. As child psychiatrist David Axelson asked, "if it is possible for children to suffer from anxiety, depression and other disorders experienced by adults, why not BP?" Moreover, they emphasize that, untreated, these children risk school failure, rejection by peers, physical injury, substance abuse, and even suicide--and their families can be torn apart.

Others at the workshop argued that BP in children is poorly defined, which can lead to misdiagnosis and inappropriate treatment. While children can have BP, they maintain that it is extremely rare and that when it is present the symptoms are very like those observed in adults. The recent increase in BP diagnoses in children is due to a redefinition of mania, key to BP diagnosis. Critics of this development hold that children are now receiving the BP diagnosis instead of one or more of the diagnoses they might have received in the past (e.g., ADHD, oppositional defiant disorder [ODD], and conduct disorder [CD], learning disorders, and pervasive developmental disorders [PDD])--or instead of some altogether new diagnosis (e.g., SMD). Some critics suggested that the BP diagnosis can be more palatable to some parents, teachers, and physicians than other better-fitting diagnoses, because the BP label attributes the child's problematic moods and behaviors to what is perceived to be a context-independent, genetic disorder. Such critics suggest that the publication in 2000 of The Bipolar Child by Dimitri and Janice Papolos [6] and a 2002 Time magazine cover story [7] precipitated a surge of parents asking physicians to give their troubled children the BP diagnosis.

Critics are also concerned about the medications used to treat BP. They observe that these drugs may not help the child, may cause harmful side effects, and increase the risk that other measures will be overlooked. Workshop participant and child psychiatrist Mary Burke speculated that, in the underprivileged community where she practices, one of the most effective ways to help children now receiving the BP diagnosis would be to promote attachment and reduce stress on families--stress that falls disproportionately on the poor [8, 9]. Consistent with Burke's point about stress as a possible precipitant of the symptoms associated with BP and other diagnoses, is the research of workshop participant and child psychiatrist Boris Birmaher (and his colleagues), which suggests that low socio economic status is predictive of worse long-term BP outcomes [10].

While there was sometimes deep disagreement at the workshop about these points and others, there was universal agreement, including from those child psychiatrists who have been vocal critics of the way in which the BP diagnosis has been applied to children, that the children at issue desperately need help. As child psychiatrist Gabrielle Carlson said, psychiatrists agree that "there is a group of children with severe irritability or affective aggression or rages whose explosive behavior is significantly impairing, that we have been chasing with different diagnoses over the years, that populate child psychiatry clinics, and that we haven't had a great deal of success in treating." Regardless of which diagnostic label is ultimately applied, the children at issue experience extreme and often debilitating moods and exhibit deeply problematic behaviors, sometimes including suicidal and homicidal rages.

Clinical reports describe chronically impaired children who are highly irritable, angry, explosive and dysphoric, often as their baseline functioning [11–13]. They may also experience racing thoughts and periods of elation, grandiosity, hypersexuality, and suicidality [14]. Vivid portraits of the suffering of children diagnosed with BP (and of the suffering these children's symptoms can cause others) can also be found in some of the more detailed media reports, including the Time magazine cover story from 2002 [15] and a 2008 feature by journalist Jennifer Egan in the magazine section of the New York Times [16].

Psychiatric diagnoses are of course based on descriptions of clusters of behaviors that everyone in a population exhibits to some degree. Human beings, through our social institutions (in this case medicine), determine when clusters of these behaviors impair functioning enough to warrant a disease label. To emphasize the role of flesh-and-blood humans in reaching those determinations, workshop participant and anthropologist Emily Martin suggested that we might speak of "living under the description of" a given psychiatric diagnosis. Martin herself is diagnosed with BP and, because she fully acknowledges the very real impact her moods and behaviors can have on her ability to flourish, she seeks treatment for the disorder. Moreover, she is keenly aware that the cluster of behaviors that we call BP has been recognized for millennia and across cultures. But in saying that she "lives under the description of bipolar disorder," Martin emphasizes the respect in which these behaviors might have developed somewhat differently, been interpreted somewhat differently, and responded to somewhat differently in a different society or time [17]. Noticing the roles of interpretation and values in making psychiatric diagnoses should make us less surprised to see controversies about whether a given set of behaviors are bad enough to warrant a diagnosis and about what "the right" diagnosis is.

There is evidence that the pharmaceutical industry plays a distressingly large role in shaping those interpretations and values [18–20]. We note in particular the concern regarding financial conflict of interest recently raised about some BP researchers. While we share many of the concerns expressed in lay and academic publications about financial conflicts of interest and the role of the pharmaceutical industry in diagnosis development [21–25], exploration of these debates could not resolve the important questions regarding diagnosis and treatment of BP that were the focus of our workshop and are the focus of this commentary.

The rate of BP diagnoses is rising faster in the US than elsewhere

Though debates about the diagnosis of BP in children can be traced back to the 1950s [26], and though Gabrielle Carlson published "Bipolar affective disorder in childhood and adolescence" in 1983 [27], the rapid increase in the number of diagnoses of BP did not begin in the US until the mid 1990s [1, 28] (see Table 1). While some symptoms now associated with the BP label can be found in previous versions of the DSM in descriptions of disorders such as "unsocialized aggressive reaction of childhood," "adjustment reaction of childhood," and "schizophrenic reaction, childhood type," DSM's description of BP did not in the past and does not now explicitly address diagnosis of this disorder in childhood.

The increase in diagnoses seems to begin with germinal 1994 and 1995 articles by Barbara Geller et al., Janet Wozniak et al. and Joseph Biederman et al., which proposed that BP was more prevalent in children than previously thought [11, 29–31]. When DSM-IV was published in 1994, it contained a new section, "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence." While this section does not specifically mention BP, it does contain the observation that "many disorders included in other sections of the manual have an onset during childhood or adolescence [32]."

Since then, diagnoses of BP in children in the community have increased in the US [1, 28]. Pre-school-age children are now among those receiving this diagnosis [2], which a short time ago was not thought to exist in early elementary school age youth (6-9 years) or even in early adolescence (10-14 years). In addition to calling attention to the increasing rate of diagnoses in children, critics have observed that the numbers are higher in the US than elsewhere and it seems that the US is the only country where BP is diagnosed in pre-school-age children. This situation suggested to workshop participant and child psychiatrist Jon McClellan (citing Soutullo et al. [33]) that something is askew in US diagnostic practices, and not, or not simply, in US genomes or environments.

While there are not good data comparing prevalence rates in the general population of children in different countries, the data comparing clinical populations (children brought to physicians' offices) reveal higher diagnostic rates in the US than many other nations. Psychiatrist and workshop member, Claudia Mehler-Wex, reported that, whereas 6% to 19% of children and adolescents in US clinical populations are diagnosed with BP [34–36], the diagnosis is virtually never made in England (1.7 cases/100,000/year)[37] nor Ireland (2.2 cases/100,000/year) [38]. Mehler-Wex reported that countries like Spain, India, Finland, Denmark, and Germany also fall well below the diagnostic rates of the US. (Brazil, where 7.2% of the clinical population is diagnosed with BP [39], is the only country with diagnostic rates close to the low end of the estimates for the US).

Mehler-Wex offered several reasons for higher rates of BP diagnoses in US children. First, DSM IV diagnostic criteria for BP cast a wider net and capture more affected individuals than do the International Statistical Classification of Diseases and Related Health Conditions 10 th Revision (ICD 10) criteria used in Europe. For example, where DSM IV requires only one episode of mania, or one episode of depression plus one episode of hypomania, to warrant a BP diagnosis, ICD 10 requires one episode of depression plus at least two episodes of mania [32]. Moreover, according to Mehler-Wex, practitioners in the US use lower thresholds for identifying symptoms than do their counterparts in Europe. Many of the children diagnosed with BP in the US would elsewhere be diagnosed with hyperkinetic disorder (roughly the ICD equivalent of ADHD), a different mood disorder, or a disruptive behavior disorder.

Another reason offered to explain higher diagnostic rates is that, as indicated by rates of stimulant and antidepressant use, US culture is in general more congenial than European cultures to psychiatric diagnoses and their pharmacological treatment in children. If, as psychiatrist Peter Kramer once suggested, the US was a country of "pharmacological Calvinists," it no longer seems to be [40].

On the other hand, workshop participant and child psychiatrist Joseph Biederman argued that nothing is "askew." His explanations for the difference in prevalence rates included: that Europeans are biased against recognizing psychiatric disorders in children that Europeans and American reporting practices lead to differences in prevalence rates that are only apparent and that US rates of diagnosis reflect a deeper understanding of the disorder among US psychiatrists.

Diagnosing psychiatric disorders in children can be challenging

Before taking a closer look at the debates in the US, we should recall two reasons that it can be difficult to diagnose psychiatric disorders in children. Psychiatric disorders are predictable clusters of emotional, behavioral and sometimes somatic symptoms that cause impairment and emerge on a spectrum. Bright lines do not separate individuals whose emotions and behaviors are and are not disordered enough to receive a BP diagnosis. Second, because different diagnoses, some of which are themselves contested (e.g., CD, ODD, PDD, ADHD, and BP) can share some of the same symptoms, deciding which diagnostic label(s) to apply to a particular patient can be challenging.

Moreover, identifying symptoms and making a diagnosis can be harder in children than in adults. Younger persons can have difficulty noticing and describing symptoms and providing accurate accounts of time of onset and duration of symptoms (although children always have a secondary informant). Further, given how rapidly children's brains develop, even practitioners can and do disagree about whether a given behavior or mood is developmentally appropriate or a symptom of disorder. Is, for example, a 4-year-old's claim that she is superwoman a sign of imagination, self-confidence, or grandiosity? If a child accompanies her claim to be superwoman with a clear indication that she is about to jump from a hotel balcony, there is good reason to infer the presence of a symptom. Other times the answer will be less obvious.

In children and in adults, it can be tempting to conclude that a given medication's ability to reduce a particular symptom confirms a diagnosis, but it does not. Gabrielle Carlson offered the example of the atypical antipsychotic risperidone (Risperdal), which is effective at reducing aggression or rages in children diagnosed with BP--but is also effective in reducing aggression or rages in children with one or more disruptive behavior disorders (ADHD, ODD, and/or CD) and below average intelligence [41] as well as in children with autism [42]. Carlson suggested that atypical antipsychotics reduce rages the way aspirin reduces fever: "Regardless of whether the underlying cause is viral or bacterial, aspirin will reduce fever. But if the patient has a bacterial illness and the aspirin masks the symptoms temporarily, you'll think you've treated something you haven't. The patient won't get the antibiotic she needs."

The DSM IV view of the BP spectrum

DSM-IV lists four BP subtypes: BP-I, BP-II, Cyclothymic Disorder, and BP-NOS [32]. In adults, the bar to getting the BP-I diagnosis is set fairly high and the classic symptoms of mania (even when mixed with depressive symptoms) are relatively easy for a well trained physician to identify. Much of the disagreement about diagnosing BP in children, however, revolves around determining just what mania looks like in children.

According to DSM IV, a full-blown Manic Episode entails "a distinct period of abnormally and persistently elevated, expansive, or irritable mood" lasting for at least 1 week. The central question in the pediatric debate is whether this episodicity criterion should be altered to include children who exhibit chronic irritability or cycle very rapidly between elevated mood and euthymia or depression. Under DSM, to meet the criteria for mania, when the patient's mood is elevated or expansive she must exhibit at least 3 of the following 7 symptoms: grandiosity, decreased need for sleep, pressure to keep talking, flight of ideas, distractibility, increased goal-directed activity, or excessive involvement in pleasurable activities that have a high potential for painful consequences. Alternatively, to meet the criteria for mania, when the patient presents with irritability, she must exhibit at least 4 of those 7 symptoms.

DSM sets the bar for BP-II lower in the sense that one does not need a full-blown Manic (or Mixed) Episode having one or more episodes of Major Depression accompanied by at least one hypomanic episode suffices. (In hypomania the symptoms are the same as in mania, but their duration is shorter--4 days instead of 1 week--and they are less impairing.) The bar is lower still for Cyclothymic Disorder because one only needs numerous periods of hypomanic symptoms and periods of depressive symptoms that do not meet criteria for Major Depressive Disorder. The Cyclothymic Disorder label, however, is rarely applied to adults or children. Finally, to receive the BP-NOS diagnosis, one does not need to meet the criteria for any of the preceding 3 subtypes of BP. For example, one may have an abnormal mood, constituted by a rapid alteration between manic and depressive symptoms, but those symptoms do not meet the minimal duration criteria for a Manic Episode or Major Depressive Episode.

Workshop discussion and debate focused not on diagnosis of those rare children who exhibit discrete episodes of mania and meet full DSM criteria for BP-I, but on whether the majority of the children described by researchers like Geller et al. and Biederman et al. were best captured by the BP label or by some other diagnosis. Child psychiatrists' thinking about these difficult-to-diagnose children has evolved in, very roughly speaking, three stages since 1994.

Stage 1: Expanding the definition of BP

Geller et al., Wozniak et al., and Biederman et al., were not the first to challenge the view that mania is rare in children, but their 1994 and 1995 papers have proved highly influential.

In 1994, Geller et al. reported that 32% of a sample of 79 children diagnosed with major depression had converted to BP-I or BP-II when followed over a 2-5 year period [31]. The following year, Geller et al. reported diagnosing 26 children aged 7-18 years with BP using a semi-structured diagnostic interview instrument [29]. They sought to define BP in a way that would allow them to cleanly distinguish it from ADHD: because one of the cardinal symptoms of mania--irritability--is also a symptom of ADHD, they would not give a BP diagnosis to children who exhibited only irritability. On their approach, for mania to be present (and for a BP diagnosis to be made), children had to exhibit elevated or expansive mood or be grandiose. Crucially, they also maintained that manic and hypomanic symptoms look different in children than in adults. Specifically, they modified DSM's criteria to allow a diagnosis of mania in children who rapidly cycled from mania or hypomania to euthymia or depression, including those who switched moods in the course of a day, and those whose symptoms did not have onset at the same time [29]. (Barbara Geller declined to participate in our workshop.)

At about the same time as Geller et al., were expanding or reinterpreting the DSM account of a manic episode characterized by elevated mood, Biederman et al. and Wozniak et al. were expanding or reinterpreting the DSM account of a manic episode characterized by irritability. In two 1995 papers, Wozniak et al. and Biederman et al. determined that 16% of their clinical population met the criteria for BP (they did not specify which BP subtype they observed)[11] primarily because of chronic irritability. They then argued that children who, based on a time-consuming structured interview, fully satisfied their understanding of DSM III criteria for mania, could also be identified with a relatively simple, cheap, easy-to-use symptom checklist, the Child Behavior Checklist (CBCL) [30]. While acknowledging the limitations of their study and the need for more research, Biederman et al. argued that, because "the clinical picture of pre-adolescent mania is very severe and impairing, there is a pressing need to refine our methods of diagnosing mania in such children (ital. added) [30]." (Critics of Geller's approach observe that 97.9% of the sample she reported in 1995 paper also exhibited irritable mood and that her later studies found rampant irritability in her sample [35, 43], raising questions about whether Geller et al. and Biederman et al. are really observing different symptoms or are simply using different terms to arrive at the same diagnosis.)

To support his group's refined or expanded understanding of childhood mania, Biederman (citing Perlis et al. [44]) observed at our workshop that about 65% of BP adults report having BP symptoms as children or adolescents that were missed by their physicians. He therefore infers that BP symptoms can look different in children, and that clinicians can miss pediatric mania if they are looking for the classic adult presentation.

Many workshop members were not persuaded by either expanded conception of mania. Aside from concerns about reinterpreting the episodicity requirement, there were also concerns about whether the observed irritable or elevated moods were properly understood as symptoms of BP. Jon McClellan, for example, was critical of what was being counted as grandiosity, noting that "Normal children display numerous behaviors and beliefs that would be considered pathological by adult standards [45]." He also suggested that many of the children Biederman et al. diagnose with BP are just "moody kids with rage outbursts and aggression." Gabrielle Carlson observed that "euphoria is easy to find if you're hunting for it, and if you infer it from merely being silly"--as one could given some of the language in the 2005 treatment guidelines for BP in JAACAP [46]. She did, however, acknowledge that episodic euphoria--euphoria that represents a dramatic shift from that child's usual mood and that appears with other symptoms--may be easier to identify.

Biederman, however, argued that in its intensity, frequency, and association with "out-of-control aggressive behavior," the irritability associated with BP is "qualitatively distinct" from the irritability associated with other childhood disorders (such as ADHD or CD). He argued that, much like a neurologist can determine the difference between a seizure associated with petit mal and one associated with temporal lobe epilepsy, so can a properly trained child psychiatrist distinguish between the different types of irritability associated with different diagnoses.

Rachel Klein argued, as she had in JAACAP in 1998, that it is a mistake to interpret chronic irritability as mania [47]. For irritability or elevated mood to count as a symptom of BP, it must appear in distinct and sustained episodes--not as chronic or rapidly cycling. As Klein put it, episodicity is a sine qua non of BP.

Stage 2. Tightening the definition of BP and beginning to define a new diagnosis

In the early 2000s, some researchers began to speak of a BP spectrum, stretching from Narrow Phenotype BP to Broad Phenotype BP. Narrow Phenotype children were largely synonymous with strictly defined BP-I patients. In 2003 Ellen Leibenluft et al., described the Broad Phenotype children:

Children exhibiting the broad phenotype may ultimately prove to be a heterogeneous group. Some may eventually meet the strict criteria for (hypo)mania the course of others' illness may be consistent with dysthymia, major depressive disorder, or some form of disruptive behavior disorder and still others may prove to have a syndrome that is not well captured by the current diagnostic system [48].

That is, while there was a small group of children who did warrant the Narrow Phenotype BP (or BP I) label, there was a larger group that would be better be captured under the rubric of Broad Phenotype BP. Some of the children in that latter, heterogeneous group might someday exhibit BP I, some might be conceptualized as exhibiting depression or a disruptive behavior disorder--and some might best be conceptualized as having a disorder that was not articulated in DSM IV. That is, Leibenluft et al. were suggesting that some children who had been receiving a BP diagnosis might be better served by a new diagnosis, perhaps called Severe Mood Dysregulation (or, as the DSM V editors are currently proposing, "Temper Dysregulation Disorder with Dysphoria") [39].

Stage 3: Severe Mood Dysregulation category gains support

As others became familiar with the SMD label, and as the data showing differences between SMD and BD grew stronger, Leibenluft et al. largely dropped the Broad Phenotype BP label. In 2006, SMD appeared for the first time in the title of a scientific article [49], describing a group of children who share severe irritability and hyperarousal symptoms with BP I children, but who exhibit chronic irritability and do not share the hallmark elevated mood or grandiosity required by the DSM diagnosis of BP I. These children were said to exhibit developmentally inappropriate reactivity to negative emotional stimuli, such as "outbursts characterized by yelling and/or aggression [28]," which occur at least 3 times a week, and are impairing in at least 2 settings (home, school, peers). To receive the SMD syndrome label, children must experience symptoms for at least a year without more than 2 symptom-free months. Onset begins before age 12 (according to Leibenluft et al.'s data, average age of onset is 5.1 years) (personal communication). A prevalence study by Brotman et al. found that SMD is relatively common in children, with a prevalence rate of 3.3% [49].

Children with SMD also exhibit ADHD- and mania-like symptoms, including 3 of the following: insomnia, intrusiveness, pressured speech, flight of ideas/racing thoughts, distractibility, and psychomotor agitation [28]. But the severity of the irritability and the intensity of mood/anxiety symptoms are greater in youths with SMD than the average child receiving the ODD and ADHD diagnoses. Moreover, the ADHD plus ODD diagnosis fails to capture the mood and anxiety symptoms that characterize SMD youths.

At our workshop, Leibenluft began to sketch the argument that SMD meets the Robins and Guze criteria for a valid diagnosis [50]. SMD children are at significantly increased risk for developing depression--not BP--at age 18 [49]. These children are less likely to have parents with BP than are children with BP [51]. When playing frustrating games, the brains of children with SMD and BP respond differently (as measured by EEG) [52]. A new study by Brotman, Leibenluft, and others, using fMRI, finds that children who have received the BP, SMD, and ADHD diagnoses exhibit unique neural correlates in emotion processing of neutral faces [53].

Some challenges were put to Leibenluft at the workshop. Biederman argued that no new nosological entity is needed because the ADHD and ODD diagnoses together adequately capture the children Leibenluft et al. are classifying as SMD. Sociologist Ilina Singh asked if part of Leibenluft's argument was circular because, by invoking emerging neuroimaging data purporting to show that the brains of children with SMD and BP function differently [28], the assumption is made that we already know just what we are trying to figure out: what SMD is. Leibenluft responded pragmatically: "You have to start somewhere. Start with observation, test, now look at brains, refine categories. It's an iterative process"

Gabrielle Carlson, who has long treated and written about children with the constellation of symptoms at issue, believes that, in addition to recognizing the difference between SMD (or BP, for that matter) and ADHD, physicians also need to recognize the possibility that children who receive one of those diagnoses might actually have a learning disorder or a PDD spectrum disorder. Such children, Carlson argued, exhibit the sorts of aggressive rages that Leibenluft links with SMD (and that Biederman links with BP). While largely agreeing with Leibenluft et al., Carlson was stressing how easy it is to miss a learning disorder or a PDD spectrum disorder, among others. In a similar vein, Mary Burke voiced the concern that some children diagnosed with BP might more helpfully be diagnosed with PTSD or what she calls "parent-child relationship disturbance" (PCRD), which in her clinical experience are often overlooked.

We recognize the magnitude of the contributions made by Biederman et al. and Geller et al.: with their research they have brought much needed attention to a group of deeply troubled children. "Diagnostically homeless children," as Carlson calls them, can be very difficult to help and to get help for from educational, medical and other support systems. Because of the way mental health and special education services are currently funded in the US, an ill-fitting diagnosis can be more helpful than no diagnosis in securing services (such as hospitalization and prescription medications) as well as disability status and other support services. Researchers, too, usually need a DSM diagnosis if they hope to find funding for their research. (We note, though, that NIMH is keenly aware of, and attempting to help researchers deal with, the ramifications of this nosological debate.) Despite these pragmatic concerns, however, we were persuaded that departing from a narrow interpretation of the DSM criteria risks confusing the discussion about the nature of the mood and behavioral problems suffered by the children at issue. We believe that a new diagnosis, along the lines of SMD, could prove more helpful to children, families, physicians and researchers. Indeed, it was recently announced that either SMD or TDD is being considered for inclusion in DSM V [54].

Why does the diagnostic label matter?

Overall treatment recommendations, monitoring, and prognosis can be different for a child diagnosed with BP and a child diagnosed with, say, ADHD, a learning disability, or PTSD. However, because the medications used to treat these different diagnoses can also be the same, one might ask: what difference does it make which diagnosis a child receives?

Gabrielle Carlson responded that even if many of the same medications are prescribed for BP and some of its diagnostic cousins, the overall treatment plans and prognoses for the children are different. For example, stimulants can trigger mania in people with BP [55], and there is evidence that antidepressants can also [56]. Conversely, children who actually have ADHD, depression, or anxiety and who are treated with the standard BP medications may experience the side effects of those medications and not improve. Moreover, because DSM's diagnostic labels are meant to facilitate research, applying them inconsistently can compromise it [57].

As Carlson also emphasized, focusing on BP can "blind clinicians to the fact that there are other things they might be focusing on." That is, because BP is associated with high heritability estimates and is treated primarily with medications, physicians may (erroneously) infer that psychosocial treatments will not be helpful, or may be less inclined to delve deeply into the quality of the child's home environment or family relations.

Complexities surrounding pharmacological treatment

As indicated by the 2007 practice parameter that appeared in JAACAP, the first mode of treatment for children with strictly-defined mania is a combination of drugs, including traditional mood stabilizers such as lithium, anticonvulsant mood stabilizers such as divalproex (Depakote) and carbamazepine (Tegretol), and the newer, "atypical" antipsychotics such as olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal). However, there are virtually no published research studies evaluating either the long-term (i.e., longer than 6 months) effectiveness or the safety of these pharmacological combinations. Support for their use is based on studies of individual medications or, in rare instances, on adjunctive treatment.

Moreover, according to some workshop participants, the efficacy of some individual medications used to treat children with BP is either unimpressive or not yet adequately established. Workshop participants Gabrielle Carlson and Julie Zito assessed the data on the efficacy of the mood stabilizers lithium, divalproex, and carbamazepine in treating children as "weak." That is, response rate (the ability to reduce symptoms of mania by 50%) in these medications did not beat placebo. Response rates for atypical antipsychotics show a better, 60-80% response with monotherapy for treatment of acute mania or mixed episodes compared to about a 25% response to placebo [58].

As the authors of the 2007 JAACAP practice parameter lament, due to limited studies in youth, "most of the treatment recommendations for early-onset BP are derived from the adult literature [59]." Of the 18 or so medications routinely prescribed for the treatment of BP, the FDA has approved only four for use in children, specifically: lithium for children over 12 years old, risperidone (Risperdal) [60] and aripiprazole (Abilify) for children over 10, and haloperidol (Haldol) for children over 3. (In addition, an advisory panel to the FDA recently recommended approval of quetiapine [Seroquel] and olanzapine [Zyprexa] for children over 13 years, although official FDA approval has not yet been made.) All other medications are used off label, including when approved medications are used to treat children younger than the specified age limits. While off-label use of medications is common in medicine, including in children, it is far from ideal. Experience with other medications has shown that because children are physiologically different from adults, medications that are generally safe and effective in adults are sometimes unsafe or ineffective in children [61–63].

Because many children with BP can also have another diagnosis (or diagnoses) such as ADHD, depression, anxiety, ODD, or OCD, additional medications may be added to the drug regimen, including antidepressants, stimulants, and first-generation antipsychotics such as haloperidol (Haldol) and chlorpromazine (Thorazine). And because every medication can have side effects, still more medications can be added to the regimen to treat the side effects.

The side-effects problem is as worrisome as it is familiar. Atypical antipsychotics are associated with extreme restlessness, uncontrollable speech and involuntary movements, and to a lesser degree tardive dyskinesia as well as drowsiness, increased metabolic problems, and significant weight gain [64–66]. The latter side effect creates additional risks, including juvenile diabetes and high cholesterol [57]. Mood stabilizers such as lithium and anticonvulsants also carry the risk of significant weight gain, drowsiness, and decreased cognition, as well as the development of tremors. Many of these medications carry risks to fetuses, leading the JAACAP practice parameter to recommend that clinicians perform adjunctive pregnancy tests and specifically warn female patients and their families about concerns regarding the anticonvulsant valproate and polycystic ovary disease [57, 67, 68].

Pharmacoepidemiologist Julie Zito pointed out that, while the complicated and difficult symptoms associated with BP call for complex treatment regimens, we know that, as a general rule, "the larger the number of medications used to treat a condition, the greater the risk of adverse events [69]." Yet, as Mary Burke suggested, "treatment guidelines support polypharmacy," as do the realities of clinical practice. "If you only have 20 minutes a month [with a child]" she argued, "it is easy to add a second antipsychotic." Joseph Biederman, however, offered reasons to explain and defend polypharmacy, including: children with BP often also have other disorders and therefore require more than one medication one drug alone may not be as effective as that drug in combination with an additional drug(s) and additional drugs are sometimes needed to treat side effects of another effective but poorly tolerated medication.

As the number of BP diagnoses in children has increased, so has the number of prescriptions in at least two of the drug classes listed above: anticonvulsants and atypical antipsychotics. In a 2009 article in Health Affairs, Stephen Crystal et al. describe not only sparse data regarding the efficacy of the newer or "atypical" antipsychotics and plentiful data regarding their metabolic risks, but they also describe a trend whereby low-income American children are as much as four times more likely than higher-income children to receive atypical antipsychotics (for BP and other psychiatric diagnoses) [70]. As Crystal et al. also say, however, no one knows at this point why poor children receive treatment with antipsychotics at such a high rate. One possible explanation has to do with social control, or an unwillingness to invest in costly non-pharmacological approaches for poor children. Another explanation would observe that because poorer children are subjected to greater stress than wealthier children, their symptomatology may be worse [71], which may make more intensive pharmacotherapy appropriate.

Julie Zito presented community-based population data at the workshop showing between 2- and nearly 6-fold increases in the use of anticonvulsants by children aged 0-19 years across a 10-year period [72]. Anticonvulsants of course also have non-psychiatric uses, but in one study Zito and colleagues reported that 81% of youth who received an anticonvulsant-mood stabilizer were prescribed it for a psychiatric diagnosis and only 19% had a seizure-related diagnosis [73].

Zito also presented demographic data showing that children taking anticonvulsants are increasingly under 13 years old, male, and African American (14% in 2004-2005 compared with 6% in 1996-1997) [74]. The same data show that 50% of the children taking anticonvulsants have a BP diagnosis, and that 38% received a stimulant, 40% an antipsychotic, 52% an antidepressant, and 12% another psychotropic medication (including lithium) in addition to the anticonvulsant. Zito et al. found that in 2004/2005 pediatricians and other non-psychiatry specialists wrote a larger proportion of anticonvulsant-mood stabilizer prescriptions for youth with psychiatric diagnosis than in the previous decade [75].

When Gabrielle Carlson asked the deceptively simply question, "Do we know if, after taking these drugs, these kids are better off?" Julie Zito answered, "We have little data on the effectiveness of treatment in community populations. I can tell you about risks from some post-marketing systems, e.g. the FDA Adverse Event Reporting System, but there is insufficient evidence of benefits in community-treated populations." Zito herself then asked, "When will we get serious about outcomes by developing the infrastructure, design and measurement protocols to provide the benefit and risk information we need to assess medication outcome in community populations [76]?"

Of course, against the potential side effects and the less-than-ideal efficacy of these agents must be weighed the risks of not treating children with prescription medications. When a child's moods and behaviors are causing her significant distress and are impairing her ability to learn, develop friendships, and participate in family life, physicians and parents may decide that medication treatment is the only, or is an important, way to stabilize the child so that her well-being can be preserved or addressed through psychosocial or educational interventions. Many workshop participants, including those critical of current prescribing practices for BP, agreed that there are times when not medicating a child carries serious risks.

Our goal here is not to assess the validity of the evidence for any drug or treatment approach. Instead we seek simply to emphasize that the facts are not as complete as families and physicians would wish them to be. Prescribing medication is always a balancing act, with physicians and parents weighing what is known about the drug's effectiveness and side effects against the severity of the symptoms the medication will target. In the case of the drugs used to treat BP (and related disorders) the balancing act can be difficult due to a lack of agreement about the diagnosis and a lack of information about the safety and efficacy of the medications. Physicians and other mental health care professionals have an ethical obligation to be honest with parents about these complexities. Policy makers, funders, and researchers have an ethical obligation to ensure that research is funded and conducted to fill these knowledge gaps.

Psychosocial treatment

There was agreement at our workshop, as there is in much of the literature, that medications will often be the first-line treatment for children diagnosed with BP or presenting the specific symptoms discussed here. However, many workshop participants also stressed that psychosocial treatments can complement pharmacotherapy, and they lamented a lack of attention to these treatments. Child psychologist David Miklowitz quipped, "We're getting to the point where psychosocial treatment is being called non-pharmacological treatment."

The workshop members who spoke about "non-pharmacological" treatments spent little time trying to distinguish among closely related diagnoses. Instead, they described different psychosocial interventions, summarized what is known about the effectiveness of these interventions at changing behavior and assisting children and families to cope with difficult moods and behaviors, and described the barriers to greater availability of these treatments.

David Miklowitz, focused on four psychosocial treatments: family focused treatment (FFT), interpersonal and social rhythm therapy (IPSRT), Cognitive Behavioral Therapy (CBT), and psychoeducation. These therapies were selected in part because they have shown efficacy in adults with BP. He explained that two or more treatments are often best used in combination because those that focus on early recognition of prodromal signs and medication adherence affect mania more than depression and those that focus on interpersonal coping strategies affect depression more than mania. Miklowitz also stressed that treatments of three or fewer sessions do not work as well as treatments of twelve or more sessions.

One target of psychosocial therapies is stress management, because stress and trauma are both contributing causes to and results of manic episodes. Psychologist Mary Fristad emphasized environmental precipitants of mania, stressing what she labeled bi-directional causation. "If you have mania" she explained, "then you create a lot of trauma in your life and trauma precipitates [mania]." It is clear that early life stress can have a lifelong impact on neurochemistry, endocrine responsivity and behavior, and adult studies have shown that early manic episodes are more likely to be triggered by stressful life events than later manic episodes [77], all of which indicates the potential value of working with children and adolescents to manage stress and trauma. Stress can include anything from the expressed emotion of family members, peers, and teachers, to hypercriticality, to sexual abuse. Unfortunately, Fristad explained, particularly given the apparently strong genetic component of BP, parents who themselves have the disorder are at increased risk for being less attentive, less active, more over-protective, and more tense, which can create stress and trauma for their children.

Miklowitz presented data from several adult studies [78], including one that compared the effectiveness of each of FFT, IRST, CBT and psychoeducation in nearly 300 adults with BP [79]. He also discussed four studies in adolescents [8, 80–82], one study of children and adolescents [83], and two studies in children [84]. In each, the study population was assigned to either psychosocial treatment(s) or a form of community or collaborative care. In all studies, the group of patients receiving one or more of the psychosocial treatment(s) was on average more likely to have (depending on the particular study's design) recovered from an acute episode of BP, experienced improvement in their levels of depression or mania, received a reduced score on a psychiatric rating scale, or improved on symptom measures. This data led Miklowitz to state that, as a rule of thumb, one or more psychosocial treatments "should accompany pharmacotherapy for early onset BP." (We are not aware of any studies that have attempted to discern whether some psychosocial interventions are more effective in children who receive the BP label versus those who receive the SMD label.)

Indeed, Miklowitz stressed that the studies cited above are just a beginning, and that more research is needed to better understand how, why, and when various therapies work. In particular, he argued that the goals of each treatment are not always clear. For example, which treatments are trying to modify treatment adherence, which family and peer relationships, and which the ability to recognize and act on prodromal symptoms? One barrier to such research is, according to Julie Zito, NIMH's failure to prioritize effectiveness research.

Cost is not only an issue in the context of research. Stephen Crystal et al. have observed that "nonpharmacological alternatives, which may involve teaching children problem-solving skills and teaching their parents to reward positive child behavior, are costly and difficult to disseminate [70]." Many workshop participants emphasized that this cost can effectively reduce the availability of psychosocial treatments and lead physicians and families to focus primarily or solely on medication. Psychosocial treatments need to be delivered by trained professionals, over a period of weeks or months, and are not always fully covered by medical insurance. Unlike appointments focused on medication management, psychosocial treatment appointments can last 30-50 minutes and may require active participation of multiple family members. While such treatments may significantly improve a child's symptoms and functioning, and while in the long term they may provide patients and their families with tools and strategies to manage and control symptoms without close supervision, in the short-to-medium term they are expensive and time consuming, requiring energy and commitment from all involved. NAMI representative Darcy Gruttadaro noted that " [while] families want more than medication, financial incentives and our stressed health care system favor writing scripts." To improve the accessibility of these therapies, health care reform must improve continuity of care and assure parity between mental health and medical services. These improvements are especially important for this difficult-to-treat population, regardless of the diagnostic labels we conclude are most helpful.

Concluding observations

Children and families can suffer terribly as a result of the serious disturbances in children's moods and behaviors described here. Because moods and behaviors are distributed continuously in a population (without clean breaks between normal enough to leave alone and atypical enough to warrant intervention), both over- and under-diagnosis are likely problems, although we did not pursue these problems at this workshop. Instead, we focused on the controversies surrounding what "actual" BP looks like in children.

In the mid-1990s, researchers led by Joseph Biederman and Barbara Geller re-described the syndrome of mania, key to any BP diagnosis. As a result, children who exhibit, in the case of Geller et al., primarily rapidly cycling elevated/expansive and/or grandiose mood, or in the case of Beiderman et al., primarily chronic irritable mood, have received a diagnosis of BP. These conceptualizations of the disorder, in combination with other social and clinical factors, have fueled a significant increase in the number of children diagnosed with and treated for BP. Insofar as everyone agrees that some fraction of these children warrant the BP diagnosis, an increase in diagnostic rates is a good thing. The debate is about how large that fraction is.

Recently, Leibenluft and colleagues have proposed that many children currently diagnosed with BP may be better thought of as exhibiting a syndrome they call SMD. In addition, other researchers and clinicians have argued that a BP diagnosis may blind physicians to or mask the presence of disorders such as severe ADHD, CD, ODD, PTSD, PDD or some autism spectrum disorders. This year, the committee responsible for writing the next iteration of the DSM proposed the addition of a new childhood disorder to be called Temper Dysregulation Disorder with Dysphoria, which is based on Leibenluft et al.'s description of the SMD syndrome.

Based on our reading in the literature and discussion at our 2-day workshop, we (the non-psychiatrist authors) were persuaded that the BP label may fit poorly many (quantification is difficult) of the children who have received it over the last decade. We were also persuaded that, when DSM IV's criteria for BP are strictly applied to children, and psychiatrists revisit the diagnosis and treatment plan periodically, the results can be potentially life-saving and may reduce years of suffering for the child and family. Clearly, more research is needed to improve our understanding of the best way to conceptualize the relationships among the different clusters of symptoms that over the last 15 years increasingly have been captured with the label BP. DSM V appears to be addressing this challenge.

We understand that greater nosological clarity may be difficult to achieve, and that an ill-fitting diagnosis can sometimes be more helpful to children, families, and researchers than no diagnosis at all. It is a deeply regrettable feature of our current mental health and educational systems that some DSM diagnoses are better than others at getting children and families access to the care and services they so desperately need.

Additional clinician training may also be needed. Symptom checklists cannot substitute for thorough evaluations. Current training practices, as well as reimbursement policies, may leave some child and adolescent psychiatrists unable to deliver the "biopsychosocial" care that so many agree is the gold standard. In addition to funds for research and training, clinical and educational resources must be available to these children and their families to relieve immediate stress and to work towards long-term recovery, symptom remission, and reduced impairment. These resources represent a significant financial burden that cannot be borne by families alone.

Given the evolving state of the research, physicians making a BP diagnosis or treating children with a BP diagnosis must remain apprised of the debates and follow the AACAP practice parameter's recommendation to revisit the diagnosis and treatment plan at regular intervals. Though we appreciate the concern regarding "truth dumping" (where a physician shares an overwhelming number of partial facts with a patient), that concern should not prevent physicians from being honest with families. Although it may initially be distressing for patients and their families to hear that a diagnosis is not universally accepted and that treatment responses are debated, providing a false sense of certainty undermines the respect for persons necessary in the physician-patient relationship. Moreover, it may cause confusion and disillusionment in the future, if the diagnosis is revised or if treatment recommendations are altered.

If physicians are to fulfill their ethical obligation to facilitate truly informed consent, they must be forthcoming with families about the relevant uncertainties and complexities. This may not be easy, but it is essential. No one should be surprised that in such a massively complex arena of inquiry, there is uncertainty and disagreement even among the most well intentioned and well informed professionals.

How does feeling stressed cause physical problems?

Over thousands of years, we have evolved a way of responding to stress that gets our body ready for physical action. This was useful when life was more dangerous. If a cave man (or woman) was attacked by a tiger, it was important that they were able to fight the tiger or run away. This is sometimes called the “fight or flight response”.

How does this work?

Our mind recognises the danger. The brain then sends signals to the body via the nerves and chemicals in the blood stream, particularly adrenaline.

These signals get the body ready for action. We breathe more quickly to get more oxygen into our blood stream.

Our heart pumps faster and harder to get blood to our muscles. Our muscles become tense so that they are ready for action.

We still have lots of stresses

Nowadays, though, we don't need to physically react to most of these stresses. For example, we may feel under stress if we take an exam, give a talk to colleagues at work, or if we need to be somewhere in hurry and our bus is late.

Our body’s stress response gets going and our body gets ready for physical action - but there is nowhere for the energy to go.

This kind of stress response can give you:

  • rapid heartbeat and palpitations
  • chest tightness and breathlessness
  • dizziness, faintness and feeling light headed
  • feeling strange or “spaced out”
  • shakiness and tremor
  • indigestion, feeling sick, diarrhoea
  • dry mouth
  • tightness in the throat
  • numbness and tingling
  • headache, muscle tension and neck stiffness
  • sweating and feeling hot or cold.

These physical symptoms of stress can feel very uncomfortable, especially if we don’t know why they are happening. They can make us feel ill.

This worry can cause even more stress and bodily symptoms, making us feel even worse … and so on. This is more likely to happen if stress goes on for a long time, as when we have money or job worries, or relationship problems.

Chronic pain

We usually feel pain when there is damage to the body. However, we can feel long-term or chronic pain, even when there doesn’t seem to be a problem with the nerves.

For example, pain can be caused by an injury, but chronic pain continues after the injury has healed.

It can be very frustrating to feel pain when there is no injury or bodily illness to account for it. We may be also be worried that people won’t believe how much pain we are in.

We think that chronic pain happens when intact nerves and areas of the brain that signal pain just seem to work wrong. (see the section above about “hardware and software”).

Pain can make us feel miserable and depressed, especially when it goes on for a long time. In turn, feeling depressed lowers our pain threshold and makes the pain feel worse.

A vicious circle of pain and depression can occur where each makes the other worse.

Applies to omeprazole: oral capsule delayed release, oral packet, oral powder for suspension, oral tablet delayed release

Side effects requiring immediate medical attention

Along with its needed effects, omeprazole may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking omeprazole:

  • Back, leg, or stomach pain
  • bleeding or crusting sores on the lips
  • blisters
  • bloody or cloudy urine
  • chills
  • continuing ulcers or sores in the mouth
  • difficult, burning, or painful urination
  • fever
  • frequent urge to urinate
  • general feeling of discomfort or illness
  • itching, skin rash
  • joint pain
  • loss of appetite
  • muscle aches or cramps
  • pain
  • red or irritated eyes
  • redness, tenderness, itching, burning, or peeling of the skin
  • sores, ulcers, or white spots on the lips, in the mouth, or on the genitals
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Blistering, peeling, or loosening of the skin
  • drowsiness
  • fast, racing, or uneven heartbeat
  • mood or mental changes
  • muscle spasms (tetany) or twitching seizures
  • red skin lesions, often with a purple center
  • red, irritated eyes
  • trembling

Get emergency help immediately if any of the following symptoms of overdose occur while taking omeprazole:

  • Blurred vision
  • confusion
  • dryness of the mouth
  • flushing
  • increased sweating

Side effects not requiring immediate medical attention

Some side effects of omeprazole may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

  • Body aches or pain
  • chest pain
  • cough or loose stools
  • difficulty with breathing
  • ear congestion
  • gas
  • loss of voice
  • muscle pain
  • sneezing
  • unusual drowsiness

Mechanisms of Depression in RA: Effects of Inflammatory Cytokines on the Brain

The pathophysiology of RA is multifactorial. The proinflammatory effects of TNF-α [49] on the function of other cytokines including IL-1, IL-6, IL-8 and GM-CSF are of central importance in the pathogenesis of RA. The circadian rhythm of inflammatory cytokines (IL-6, TNF-α) and glucocorticoids explains a worse disease activity of RA in the early morning [50]. T cell differentiation and T helper (Th) cells, CD4 + cell differentiation, formation of Th1 cells and secretion of IFN-γ [51] stimulated by IL-12 are responsible for T-cell-related RA flares. IL-23 together with IL-17A, IL-1 and IL-6 induces systemic and local inflammation in RA [52, 49]. The correlation among fatigue, depression and the mechanism of cytokines in autoimmune diseases was shown in cross-sectional trials [5].

There are many hypotheses regarding how peripheral cytokines, local inflammation and swelling induce the inflammation of extra-articular tissue and cerebral inflammation. A significantly higher level of IL-1β, IL-6 and TNF-α in RA predisposes to extensive atherogenesis [54]. IL-1 and IFN-alpha enhance the release of tryptophan metabolites and oxidative stress, causing delayed neurogenesis and fatigue [56]. Peripheral inflammation and cytokines IL-1, IL-6 and TNF-α transmit signals to the brain via either primary afferent neurons [57] or the endothelial cells of cerebral vessels where IL-1 acts on macrophage-like cells in the CNS, disturbing neural integrity where the blood brain barrier becomes less intact [11, 25]. Chronic inflammation can interfere with glutamate neurotransmitters causing neurocircuitry malfunction at the glia [58]. Neuroinflammation and microglial activation associated with systemic inflammation were seen on PET imaging in the cases of systemic inflammation in a small preliminary study [59].

Fatigue and Cytokines

IL-6 activates the HPA axis without a compensated production of cortisol, resulting in fatigue [60]. The aetiology of fatigue in RA has been widely explained by the effect of cytokines [61, 62] IL-1β, IL-2, IL-6 and TNF-α on the function of noradrenaline, dopamine and serotonin through monoamine transporters in neurons. The effect of dopamine and serotonin on the mesolimbic pathway responsible for anhedonia can cause “motivational fatigue” whilst abnormal dopamine action on the nigrostriatal pathway is associated with “physical fatigue”, and noradrenergic-dopaminergic action on the mesocortical pathway interferes with concentration and short-term memory causing “cognitive fatigue” [24].

Depression and Cytokines

Advances in “immunopsychiatry” have established a better understanding of the relationship between depression and inflammation, and over the last 2 or 3 decades, some have considered depression an inflammation-related disorder (Fig. 1) [63]. Increasing levels of IL-1, IL-6, C-reactive protein and TNF-alpha in T-cell-mediated inflammation were found in patients with depression or anxiety [64]. HPA axis dysregulation by IL-6 may lead to anxiety and depression in RA patients [60]. The level of IL-17A has also been shown to be highly associated with the severity of depression [65]. CRP is a strong indicator of disease activity in RA [54], and a high level of CRP induces anhedonia by inhibiting the function of the ventromedial cortex of the brain [66]. In children with inflammatory medical conditions, the risk of depression in adulthood may be high because of permanent effects as a result of early exposure to stress, high levels of CRP, and raised leucocyte count and IL-6 [67]. An increased level of IL-6 in CSF is associated with a decrease in serotonin metabolites, which contributes to depression, but no relationship between IL-6 and catecholamines has been found [68]. A raised IL-6 level for ≥ 6 months plays an important role in the occurrence of depression [66], and more suicide attempts are seen in people with an increased CSF IL-6 level [67]. In RA, inflammatory markers including CRP, ESR and pro-inflammatory cytokines TNF-α, IL-1, Il-6 and IFN-α levels are elevated, and such increased levels of inflammation are regarded as a “biological scar” that increases the risk of depression [69].

Adapted from “Impact of Inflammation on the Brain and Behaviour” [63] with the respective assessment tools

Cognitive Function and Cytokines

Cognitive impairment may occur in RA patients because of the direct effect of inflammation on the brain, the impact on cerebral blood vessels in the same way as cardiovascular complications or adverse effects from glucocorticoids and immunosuppressants [70]. Pain, fatigue, anxiety and depression are also responsible for cognitive dysfunction. Cytokines released in RA cause systemic inflammation and can interfere with mood, cognition and sleep [27]. Bartolini et al. reported in their cohort study that 38–70% of RA patients have cognitive impairment [71]. A study performed by Shin et al. used the American College of Rheumatology neuropsychological battery modified for RA to assess cognitive function scores in 144 RA patients, and the results showed cognitive impairment in executive function, visuo-spatial learning and verbal memory as > 20%, 29% and 18% respectively [72]. A cross-sectional study assessed cognitive function using the Montreal Cognitive Assessment (MOCA) on 60 female RA patients taking MTX or bDMARDs, and the results showed > 60% RA patients scored MOCA < 26 (normal ≥ 26) compared to 49% in the control group [73]. Another study that measured the Mini Mental State Examination (MMSE) score, level of depression, VAS and DAS28 reported the correlation between a low level of MMSE and VAS but not between depression and cumulative steroid dose [74].

RA Therapies: Impacts on Fatigue, Depression and Cognition

RA is treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs), biologic (b) DMARDs, targeted synthetic (ts) DMARDs and glucocorticoids [8]. An open-label cohort study found that bDMARDs improve depression in RA patients [75]. Another prospective single-blinded study reported that csDMARDs and bDMARDs have a similar effect on improving depressive symptoms in RA patients [76].

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

A systematic review of 30 randomised controlled trials (RCTs) showed that NSAIDs alleviated symptoms of depression [standard mean difference (SMD) − 0.55, 95% CI − 0.75 to − 0.35] compared to the placebo arm [77]. A negative association between long-term NSAID use and depression [HR (95% CI): 0.20 (0.04–0.87)] but a non-specific statistical correlation on repeated testing is seen [78]. Celecoxib, the selective COX-2 inhibitor, showed evidence of improving anhedonia and symptoms of depression in a rodent model (P > 0.05 compared to fluoxetine) [79]. Aspirin and N-acetylcysteine combination therapy improved symptoms of bipolar disorder in 67% of patients [80].


The glucocorticoid receptor is important in maintaining the function of the hypothalamic-pituitary-adrenal (HPA) axis, which is responsible for the occurrence of depression. An experimental study showed that prednisolone acetate 40 mg/kg can induce depression-like behaviour in rhesus macaques [81]. Exogenous corticosterone can cause induction of glutamate at synapses, which contributes to mood disorders [82, 83]. Cognitive decline is found to be related to current or long-term steroid use (even low dose) in RA patients as a vascular side effect [72] but another study reported no significant relation between MMSE and chronic glucocorticoid use [74].


The health-related QoL (HRQoL) is significantly low in RA patients compared to the general population pain and fatigue are the main contributing factors [1]. The effect of csDMARDs on QoL, functional status, anxiety and depression in RA patients is not inferior to that of bDMARDs [76]. RA patients taking methotrexate or leflunomide were found to have lower risk of self-harm behaviour compared to those taking hydroxychloroquine or biologics, patients on leflunomide being the lowest-risk group of having anxiety or depression [84]. One RCT proved that MTX, LEF and SLZ improve physical function, mental impairment and QoL in RA patients by measuring SF-36 and HAQ, the difference in mean or median HAQ-DI being − 0.22 at the 12- and 24-month period [85]. Another RCT proved the superior effect of LEF over placebo in improving bodily pain, functional status, PGA, SF-36 score and HAQ-DI. A better statistically significant result with MTX versus placebo was also found in the trial [86]. Microglial activation and corpus callosum were detected in a juvenile rodent model study and it also showed cognitive decline after 1 week and 8 weeks of methotrexate 0.5 mg/kg injection [87]. An improvement in HAQ-DI (mean 1.46 from baseline 1.63 p = 0.001) in 3 months is seen in RA patients treated with leflunomide [88].


Depression as a comorbidity in RA patients before starting on bDMARDs can reduce the treatment response [31]. The BSRBR reported a DAS28 difference at 1-year follow-up for patients treated with bDMARDs as − 0.38, − 0.34 and − 0.32 in no, moderate and severe depression respectively measured by EQ5D [31]. Odd ratios (ORs) for a good treatment response at 1-year follow-up between no depression patients and moderate depression patients showed OR = 0.85 (95% CI 0.69, 1.04) whilst between no depression group and severe depression group showed OR = 0.62 (95% CI 0.45, 0.87) [31].

IL-6 has a significant relationship with major depressive disorder (MDD) [66], and IL-6 inhibitors are considered effective in selective serotonin reuptake inhibitor (SSRI) refractory major depression cases [67, 66, 68]. Sarilumab, by targeting IL-6, improves depression in RA patients [60]. It is also evident that sirukumab targeting IL-6 and reducing the CRP level improved major depressive symptoms [89]. An observational study showed a positive correlation between the FACIT-F score and depression (BDI scale) (linear regression β = 0.714 and β = 0.777) (p < 0.001). The percentage of RA patients with fatigue was reduced from 58.8 to 37.6% in 6 months after receiving tocilizumab (TCZ), reducing the FACIT-F scale by 5.4 ± 11.2 (p < 0.001) from baseline [90]. An improvement in HAQ-DI and PGA is also found in RA patients on TCZ [91]. A retrospective study showed depression remission (HAM-D < 7) in bDMARDs-treated young female RA patients [41]. Fiftty per cent improvement in depressive symptoms through glucose and lipid homeostasis is seen after 12-month treatment with infliximab [92].

Tumour necrosis factor inhibitor (TNFi) therapy has been shown to improve fatigue and reduce emotional stress and cognitive function [93]. A reduction in the level of fatigue (FACIT-F and SF-36) is reported by standardised mean difference − 0.42 (P < 0.00001) for TNFi and − 0.46 (P < 0.00001) for non-TNFi bDMARDs [47]. A small and moderate improvement in FACIT-F with TNFi (adalimumab, golimumab and certolizumab) and with non-TNFi biologics was found the effect size (ES) was 0.36 (95% CI 0.21, 0.51) and 0.57 (95% CI 0.39, 0.75) respectively compared to placebo group [94].


Significant reductions in fatigue with JAK inhibitors tofacitnib and baricitinib were also proved in phase 3 clinical trials. The improvement in FACIT-F score was seen at 24 weeks for patients taking baricitinib 4 mg but no statistical significance with 2 mg baricitinib according to randomised controlled trials [47, 95]. ACR20, ACR50 and ACR70 response criteria were fulfilled in patients taking baricitinib 4 mg at week 12 [95]. In > 68% of RA patients treated with tofacitinib monotherapy, MTX + tofacitinib and adalimumab(ADA) + MTX in a phase IIIB/IV study, an overall improvement in QoL (FACIT-F, SF-36, PGA and HAQ-DI) was observed [96]. All three groups reported significant improvement in arthritis pain at week 6, least square mean (LSM) changes being − 22.6 in tofacitinib monotherapy, − 22.8 in the tofacitinib + MTX group and − 23.0 in the ADA + MTX group. Reduction in pain score among tofacitinib monotherapy patients was sustained at 3 months (p < 0.01), at 6 months (LSM change − 26.6, p < 0.05) and at 12 months (p < 0.05) [96]. Tofacitinib was proved to be superior to methotrexate in improving PROs in a phase 3 RCT [97]. The results from the SELECT-NEXT RCT showed that upadacitinib 15 mg or 30 mg in RA improved all PROs including SF-36, FACIT-F, PGA, pain VAS score, EMS and HAQ-DI in 12-week duration from baseline [98].

Adapting to the current economic times

It’s really sink or swim, fly or fall, eat or be eaten, adapt or get left in the dust these days in regards to the economy, which makes it tough for many people. From a historical perspective, many people held cushy jobs that allowed them to earn a healthy living without actually contributing much to society. Now that those jobs are becoming obsolete and companies are downsizing, it’s becoming more difficult to find work unless you have skills to fit the fast-changing economic times.

Additionally with a growing population and increased demand for technological-related skills, older generations are having a tough time finding work. The unfortunate reality is that if you are unemployed, you need to find something to fill that emotional void. Sure it’s about making enough money to support yourself, but the other aspects that come with a job such as social interaction (even if they aren’t positive interactions) keep the brain alert and stimulated and are often underrated.

Lack of social stimulation over a prolonged period is downright unhealthy and could lead to various forms of neurodegeneration. The age old adage in regards to personality seems to apply: “if you don’t use it, you lose it.” The less you express certain personality traits, the less likely you will be able to use them in the future. Similarly with your work-related skills, the less you use them, the more likely you are to lose them – all of which decrease your value in the eyes of an employer.

If you are unemployed, find a new job as soon as possible for not only the finances, but the socialization that accompanies it. You could be preserving many positive personality traits by getting a job as soon as you are unemployed. The longer you wait, the tougher it will be not only for you to find work, but to maintain positive personality traits such as: agreeableness, conscientiousness, and openness.

Related Posts:

Everyone is on their own journey. Committing suicide may put you out of misery but will shift the pain over to people that love you deeply. Please do not do that to someone. There are answers out there even if it has been years trying to find it.

I too am unemployed and struggling with depression. I feel worthless and rejected. But I will not shift that over on people that love me. I will continue to hope for an answer. I believe we are all on this earth for a positive reason. Maybe I have asked but not listened. I will continue to search.

Although this article raises awareness, it’s essentially useless to those of us living through it. I’ve been unemployed for 5 years and am now 50 years old. Nobody will even give me the time of day. I’m suicidal every freaking day. I don’t WANT to kill myself, I just want to go back to being a contributing member of society.

I had a successful career for 30 years… why the hell won’t anybody hire me? Since nobody will hire me, I’m forced to think about ending my life daily… and to think… I used to be the biggest optimist.

You are not alone. It is not your fault. For those of us so affected, NOTHING makes ANY sense anymore. I hope you’re still hanging in there. (((BIG HUG)))

I can’t help myself from chiming in too. I lost my last full time professional job in 2010, at 53, when some co-workers who disliked me wrote a resignation letter for me and it was accepted by the director, even though I hadn’t signed it. I won a lawsuit against the individuals involved, but that did nothing to help my circumstances. Once you are in that kind of spot, you become a leper to future employers.

Since then, I have taught driver’s education, filled in seasonally at UPS, clerked at a library. I have been turned down for jobs at Kroger”s, Giant Eagle, Rite Aid, and similar retailers. I will be 60 this summer. That I am a body building, youthful individual with lots of curiosity and willingness to learn has not helped me an ounce.

I feel that I have sunk deeper into lack of enthusiasm for any job I apply for, already imagining my efforts to be a waste of time. I recently started volunteering at a place I would love to work, although I have no unrealistic vision of that actually happening: the others are at least a decade or two younger than me. I was accepted into a certificate program in what used to be my field. The classes start this summer (2017).

I applied with a spark of hope that maybe there will be some helpful connections there. Of course, I will likely have another student loan, if I don’t find a scholarship for older women. The next thing is to see if my medicaid covers therapy. I guess just being able to stop living with self-doubt would be a big accomplishment.

A lot of the time I feel like a fool for allowing myself to think positively and imagine a group of younger people would actually want me around. I know what you mean about wishing to contribute again. I don’t know what the answer is.

Like all studies it is prone to bias. My suggestion is simple this. Whomever carried out this research really does need to get a proper job and actually contribute something to society rather that depressing us all.

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Can CIPN be treated?

Treatment can often help ease some of the symptoms of CIPN. Sometimes these symptoms go away a short time after treatment is done. But sometimes they last much longer and need long-term treatment. Severe CIPN may never go away.

Treatment is mostly given to relieve the pain that can come with CIPN. Some of the drugs used include:

  • Steroids for a short time until a long-term treatment plan is in place
  • Patches or creams of numbing medicine that can be put right on the painful area (for example, lidocaine patches or capsaicin cream)
  • Antidepressant medicines, often in smaller doses than are used to treat depression
  • Anti-seizure medicines, which are used to help many types of nerve pain
  • Opioids or narcotics, for when pain is severe

Researchers are looking at which drugs work best to relieve this kind of pain. It may take more than one try to find out what works best for you.

  • Electrical nerve stimulation
  • Occupational therapy
  • Physical therapy
  • Relaxation therapy
  • Guided imagery
  • Distraction
  • Acupuncture
  • Biofeedback

Treating Persistent Depressive Disorder

Persistent depressive disorder (previously known as dysthymia) is a long-lasting depression. It can feel as if it’s just part of who you are — but it doesn’t have to be.

Though not as common as depression, persistent depressive disorder (PDD) affects many people worldwide. Estimates suggest that 1.3% of adults in the United States experience this condition at some point in their lives.

PDD was previously known by two other names: dysthymia and chronic depression.

This condition often goes untreated. People may think that because they’ve lived with the symptoms for so long, it’s just part of who they are, or there’s no fixing whatever is “wrong” with them.

As the name suggests, persistent depressive disorder is persistent, so treatment won’t happen overnight — but there are many types of support and options on your side.

Treating persistent depressive disorder (PDD) is a lot like treating other types of depression. The best treatment is typically a combination of therapy, medication, and self-help strategies. You can learn more about these treatments below.

Psychotherapy — aka talk therapy — aims to help you manage your symptoms, constructively deal with problems in your life, and support you in your treatment.

There are several types of therapy for PDD.

Cognitive behavioral therapy

Cognitive behavioral therapy (CBT) is well-known for treating depression, among other mental health conditions.

One goal of CBT is to help you “rewire” your thoughts. Many people with depression experience distorted ways of thinking, which may be even more ingrained if you have persistent depression.

Your thoughts may automatically go to places like “I will never get better” or “I’m a failure,” which can make you feel worse. A therapist can help you learn to recognize these distortions and change your outlook.

  • explore how your emotions, thoughts, and behaviors affect your life and actions
  • problem solve
  • learn coping skills and relaxation techniques


Cognitive behavioral analysis system of psychotherapy (CBASP) is a newer therapy specifically developed for managing chronic depression.

CBASP combines elements of other therapies, like CBT, with psychodynamic and interpersonal strategies.

The goal of this therapy is to:

  • learn to recognize the consequences of your behaviors
  • develop social problem-solving skills
  • grow interpersonal skills and empathy
  • improve functioning and decrease isolation

Research is ongoing for this therapy, and it may not work well for everyone. It’s not as well known as therapies like CBT, so it may be more difficult to find a mental health professional who offers this treatment.

Interpersonal therapy

Interpersonal therapy (IPT) is a form of talking therapy that focuses on social and relationship problems that may contribute to the persistence of depression symptoms.

The goals of IPT are to help you communicate better, address relationship issues, and deal with difficult emotions in more positive ways.

Radically open dialectical behavior therapy

Radically open dialectical behavior therapy (RO-DBT) is a newer type of therapy that’s shown promise for chronic or treatment-resistant mental health conditions.

Dialectical behavior therapy (DBT) is at the base of RO-DBT. This is a type of psychosocial therapy that helps you cope with difficult emotions.

RO-DBT is considered for people who “overcontrol” or attempt to cope by self-controlling. Overcontrol has been linked with social isolation and other relationship problems, perfectionist tendencies, and suppressed emotions.

Though this therapy may help some people with PDD, it is new and may have limited accessibility.

First-line treatments for PDD usually combine medication and therapy.

The medications for PDD are the same as those that treat other forms of depression. These include:

    , such as fluoxetine (Prozac) or sertraline (Zoloft)
  • serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor) or duloxetine (Cymbalta)
  • atypical antidepressants, like bupropion (Wellbutrin)
  • tricyclic antidepressants (TCAs), including amitriptyline

Most doctors will likely start by prescribing an SSRI since most people tolerate them well, but it’s not uncommon for people to try several medications before finding one that works for them.

It’s not always easy to find the right med that relieves symptoms without causing too many side effects. Treating chronic depression may also involve some maintenance, which means tweaking the treatment over time.

While it can be a frustrating back and forth of trial and error, there are treatments out there that will help you.

There are a lot of things you can try to relieve some of your depression symptoms — from support groups to supplements, stress relief, and sleeping habits.

Since PDD is so long-lasting, making habit changes may help you learn how to cope and live better in the long term.


You don’t need to do this alone. Support can come in so many forms.

It often helps to reach out to loved ones, medical professionals, and support groups. These people can offer different types of support. Mental health professionals can help keep you on track with your treatment plan, while loved ones can learn how to support you in a crisis or join you on a weekly walk.

  • Visit Mental Health America’s support group database.
  • Join an online support group through the Depression and Bipolar Support Alliance.
  • Find a support group or family support group through the National Alliance on Mental Illness.

Exercise and eating

We’ve all heard that eating well and exercising can improve overall health, but it may also help with depression.

With PDD, making the decision to slowly add healthier foods or movement into your day may help you feel better in a lot of ways.

When it comes to exercise, the feel-good hormones that are released can boost your mood. Some evidence also suggests that it can help reverse physical effects of depression by improving your body’s response to stress and regulating your appetite.

You don’t have to start with a gym membership or daily weight lifting. Any movement is beneficial, so consider a short walk or 10 minutes of morning stretching.

As for food choices, it’s best to avoid strict diets that can be hard to follow. Instead, consider adding healthier foods slowly, finding what you like best and what’s accessible to you. Your choices could include:


It’s not uncommon to sleep too little or too much when living with depression.

While you’ll want to speak with a healthcare professional if you’re really struggling, you can also follow some tips for good sleep hygiene:

  • Consistent sleep schedule. Going to sleep and waking at the same times, even on weekends, can be helpful. This may help you achieve a goal of 7 to 9 hours of sleep.
  • Comfortable sleep environment. If possible, keep your bedroom dark and reserve it only for sleeping. If there’s outside noise or distractions, a sleep meditation podcast or white noise may help. In the morning, pulling back the curtains will allow some natural sunlight.
  • Routine before bed. This can look like whatever you want it to. One idea could be brushing your teeth, setting out your clothes for the next day, and reading a chapter in a book. It can help to avoid screens at least an hour before bed.

Stress-relieving activities

While everyone gets stressed, if you’re living with chronic depression, stress can make it even harder than usual to cope.

Here are some stress-relieving activities:


Evidence on the effectiveness of complementary medication for treating depression isn’t consistent. Nevertheless, you’ve likely heard of at least a few and wondered if they could help.

If you’re interested in supplements, your doctor may have suggestions. But know that some supplements can interact with your current medications or produce unwanted side effects.

St. John’s wort

This wild plant, hypericum perforatum, has often been touted for treating depression, although most evidence on St. John’s wort for depression is mixed.

St John’s wort can affect many medications, though, such as antidepressants and birth control pills. Consider talking with a healthcare professional before you try it. It’s also a stimulant and could intensify anxiety in some people.

S-Adenosyl-L-methionine (SAMe)

This chemical is naturally made in the body and helps regulate cell functioning. Abnormal levels have been reported in some people with depression.

Small short-term trials have shown some benefit, but research is still inconclusive.

Vitamin D

Many people are deficient in vitamin D. According to one source, as many as 1 billion people lack enough. Some research suggests an association between vitamin D deficiency and depression.

Though you can get vitamin D from sunshine (which comes with its own mood-boosting benefits), many doctors support supplementation as well.

Omega-3 fatty acids

These essential fatty acids are found in fatty fish, seeds, and nuts but can also be taken as a supplement.

Omega-3s have a lot of benefits, which may include improving depressive symptoms. But the cause of your depression and severity might make a difference in if omega-3s will have a benefit for you.

N-acetylcysteine (NAC)

This is a type of amino acid. Some research has found that it shows promise for improving daily functioning and helping with depressive symptoms — not to mention it seems fairly well tolerated.

Several other treatments may be recommended depending on the severity of your depression or if you haven’t responded well to first-line treatments.

  • Light therapy. If you have a hard time getting out of bed due to your depression, or your symptoms are affected by the seasons, you may find a light therapy box to be helpful. A light box can compensate for a lack of sunlight and may help with sleep and serotonin levels.
  • Repetitive transcranial magnetic stimulation (rTMS). rTMS is a type of brain stimulation therapy that’s less invasive than most others. Research is still ongoing, but the therapy has shown promise for its antidepressant qualities, at least for people with treatment-resistant depression.
  • Electroconvulsive therapy (ECT).ECT is one of the most effective types of brain stimulation therapy. Doctors still don’t typically recommend it as a first-line therapy as it can cause memory loss and requires you to be under general anesthesia.

You may know persistent depressive disorder by a different name if you were diagnosed before the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) came out. PDD is a combination of two conditions: chronic major depressive disorder and dysthymic disorder.

According to the DSM-5 criteria, you might receive a PDD diagnosis if you’ve experienced depression most of the time for at least 2 years. In children and younger people, you need to have experienced symptoms for at least 1 year.

Along with depressed mood, at least 2 of the following symptoms must occur:

  • appetite changes either overeating or loss of appetite
  • oversleeping (hypersomnia) or difficulty sleeping (insomnia)
  • tiredness and low energy
  • low self-esteem
  • difficulty with decision-making and lack of concentration
  • feeling hopeless

As with most mental health conditions, diagnosis occurs when symptoms interfere with your daily life and functioning.

Symptoms will also need to be present continuously, without more than 2 months of being symptom-free in the 2-year period.

Your doctor or a mental health professional will also eliminate other potential causes for your symptoms such as:

    , a type of bipolar disorder
  • persistent schizoaffective disorder
  • using certain substances or medications
  • a medical condition, such as hypothyroidism

If you think you may have PDD — or any depression — you can reach out directly to a mental health professional or your primary doctor if that feels more comfortable.

The more information you have for your doctor, the easier it will be to eliminate other causes, diagnose a condition, and get you started on a treatment plan that will have some success.

You can better prepare for your appointment by making a note of your symptoms. For example, try to make a note of your symptoms, how long they have been present, and how they affect your life.

Information you can bring with you includes:

  • A list of the main symptoms you’ve been experiencing.
  • How long and how severe these symptoms are.
  • Where the symptoms interfere with your functioning: Is it harder to work, focus, wake up or sleep? Are you overeating or never hungry? Do you also have anxiety or really “high” moods along with lows?
  • A current list of medications or supplements you take.
  • Your medical history, either conditions you have or anything that may run in your family.

Dealing with persistent depressive disorder can be challenging because of how long-lasting its symptoms are. You might feel as if it’s just how life is for you — but it doesn’t have to be.

Between first-line treatments like medication and therapy, along with so many coping tools — support groups, stress-relieving techniques, breathing exercises, and more — you can find a combination that will help manage your PDD.

Social anxiety disorder usually begins in the teenage years although it may start in childhood.   While the exact cause of SAD is unknown, it is believed to result from a combination of both genetic and environmental factors.

Imbalances in brain chemistry have been linked to SAD. For example, an imbalance in the neurotransmitter serotonin, a brain chemical that regulates mood and emotions, may play a role in the development of social anxiety disorder.

Over-activity of a structure in the brain called the amygdala has also been linked to social anxiety.   People with SAD may be predisposed to an exaggerated fear response and, in turn, increased anxiety.

Several environmental factors may also increase your risk of developing SAD. These include but are not limited to:

  • Having an overly critical, controlling, or protective parent  
  • Being bullied or teased as a child
  • Family conflict or sexual abuse
  • A shy, timid, or withdrawn temperament as a child