The science of Selective Serotonin Reuptake Inhibitors (SSRI): theory, efficacy, and dangers. Review prepared by Dan L. Johnson as background regarding Dexter’s case.
Fluoxetine, like other SSRIs, is associated with suicide in adolescents and adults, and is only slightly more effective in treatment of depression than placebo, with a small effect size (the difference between treatment and placebo). In some cases, the effect size is so small that “no clarification is given what this effect size means and whether it can be expected to be clinically significant in real-world routine practice.” (Hengartner and Plöder 2018).
The widely but sometimes mistakenly believed existence of a link between serotonin concentration and depression via a “chemical imbalance” is not supported by evidence from any well designed studies. Dr. Glen Spielmans, Professor of Psychology, Metropolitan State University, Saint Paul, MN said “the FDA statistical reviewer concluded that fluoxetine did not demonstrate efficacy, since it did not outperform placebo on the primary outcome measure. Yet FDA approved it anyway. Then, many folks misconstrued this approval as clear evidence of efficacy/safety for treating youth depression. All network meta-analyses of antidepressants are, to put it charitably, highly compromised.” (recently confirmed, pers. comm.)
Serotonin is a monoamine neurotransmitter found in many vertebrate and invertebrate animal systems, evolutionarily old and even important in crustaceans and insects. Serotonergic neurons are present in most living things with nervous systems, where serotonin modulates nerve function and behaviour. Neurons have serotonin receptors that allow them to function and reset. SSRIs block the serotonin reuptake transporter and this results in a higher concentration of serotonin in nervous tissue and the brain (and subsequent feedback that re-regulates the levels, until more SSRI is applied). Selective serotonin reuptake inhibitor antidepressants were introduced in the 1980s, based on the hopeful idea that depression might be caused by a problem with serotonin quantity and fate or some other “chemical imbalance”, a hypothesized condition that could be corrected with an SSRI medication. Years of efforts to find evidence in support of the idea have failed, causing some leading psychiatrists to call it an “urban legend” (Ang et al. 2022), even causing former believers to say “I have tried to drive a stake through the heart of two myths regarding the so-called ‘chemical imbalance’ theory – but with only limited success” (Pies 2019a,b). SSRIs do not have an action or mechanism that cures any underlying cause of depression. David Healy (2015) summarized it:
“...Drug companies marketed SSRIs for depression, even though they were weaker than older tricyclic antidepressants, and sold the idea that depression was the deeper illness behind the superficial manifestations of anxiety. The approach was an astonishing success, central to which was the notion that SSRIs restored serotonin levels to normal, a notion that later transmuted into the idea that they remedied a chemical imbalance. ... There was no correlation between serotonin reuptake inhibiting potency and antidepressant efficacy. No one knew if SSRIs raised or lowered serotonin levels; they still don't know. There was no evidence that treatment corrected anything.”
For a while, psychiatry and psychology textbooks, including those used in medical schools, promoted or implied that a chemical imbalance might cause depression, for which the cure could be an SSRI. In recent years, studies, experiments, and careful reviews of findings show again and again that there is no consistent evidence that depression is associated with serotonin (Ang et al. 2022, Moncrieff et al. 2022). However, the brain-numbing effect and emotional blunting that results from use of SSRIs may seem like an improvement to some people (mainly adults), which might be the cause of apparent improvements when taking Prozac, which in some studies is slightly better than, or overlapping with, the results of placebo. It has taken time to sort out, in part because of the small differences when it does seem to do something. The improvements are found with either placebo or antidepressants, and the differences are very small. Only about 15% of (adult) participants have a substantial antidepressant effect beyond a placebo effect in clinical trials (Stone et al. 2022). Some previous studies were missing information and were biased by exclusions of some subjects and missing data, allowing a conclusion of slight efficacy even while ratings by patients did not find fluoxetine effective. Extensive reviews over the last decade of a range of possible evidence indicate no relationship between depression and serotonin. Moncrieff et al. (2022) reviewed the studies in greater detail, and found essentially the same answer, yet again and in greater detail:
“The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.”
Some guidelines recommend talk therapy first. The American Academy of Child and Adolescent Psychiatry and the American Psychological Association guidelines recommend talk psychotherapy or CBT (cognitive behavioral therapy). Some evidence has been found that even when fluoxetine is prescribed, it should be used together with CBT. The Canadian Paediatric Society does recommend SSRIs over no treatment at all, but emphasizes that “patients should be closely monitored for potential adverse effects, including suicidal ideation and behaviour.” The question of risks and benefits is more and more important, as previous reviews and more recent comprehensive reviews have found that there is no scientific evidence for the biological model of depression based on serotonin imbalance (Moncrieff et al. 2022).
Although fluoxetine (originally marketed as Prozac) does not cure an underlying cause of depression or correct an imagined initial chemical imbalance, it certainly does alter brain chemistry after it is taken, with resulting changes in behavior and a likelihood of developing dependency. The history of development and impacts of SSRIs is reviewed by Whitaker (2015) and Healy (2004, 2020). Increased suicide rates while taking antidepressants have been reported for a long time (Creaney et al. 1991; Teicher et al. 1990). The mechanism is unknown for the increase in suicidal ideation, and in some cases resulting drug-induced behavioural disinhibition (Bond 1998; Hoehn-Saric et al. 1990). Early tests by Eli Lilly were criticized in discussions of experimental design and analyses that favoured finding fluoxetine to be safe and effective (Creaney et al. 1991; Oswald et al. 1991). In 2004, the US Food and Drug Administration (FDA) ordered drug companies to place a black box warning on all antidepressants, stating that suicidal behaviour might increase in children and adolescents taking the drugs and that monitoring is required, indicating that families and caregivers must be advised. The risk is real. Michael Hengarter, a psychologist and senior lecturer at Zurich University of Applied Sciences, has extensively investigated antidepressant studies and data, concludes: “The issue whether AD increase the risk of suicidal ideation and behavior in minors and young adults has long been settled, which is why all major drug regulatory agencies issued a serious safety warning.” (recently confirmed, pers. comm.)
Some manufacturers admitted an increase in suicidal behaviour in patients taking SSRI antidepressants. GlaxoSmithKline (Lenzer 2006) announced that they had found an increase in suicidal behaviour in adults taking paroxetine compared with placebo, in clinical trials.
In some cases, the suicide ideation effect is apparent even when healthy volunteers with no depression take SSRI antidepressants. The Medical Research Information Center Global recently published a personal story by a physician in Japan who tried the SSRI Paxil (paroxetine).
“...Although I had only been taking it for three days, I was haunted by suicidal thoughts like 'the elation that death is a comfort.' I was in a daze for a few days. I took it for only three days, but I thought about death a lot for some reason. It was a strange experience: ‘If I put a string on the handle of a chest of drawers, I could die, and my wife would have to die with me.’ I had no fear of death, no sense of reality at all. … my son, a pharmacology student, warned me about the dangers of SSRIs.” (Setsuo Ide Paediatrics, Kagoshima Prefecture)
Cases noted early in the history of fluoxetine raised red flags. Settle and Settle (1984) reported on a case, “A depressed woman with no history of bipolar illness developed a manic episode during treatment with fluoxetine. This side effect appears to be a universal property of effective antidepressants, including this new, purely serotonergic agent.”
Healy (2000) noted “...those who did not suffer from a psychiatric illness may have been at more risk from this drug than others. This healthy volunteer study suggests that individuals who are not frankly depressed may also be at increased risk of drug-induced problems compared to others.”
This is counter to the view that the underlying condition that resulted in the medication caused the adverse effect, so-called “confounding by indication”, which calls into question drug side effects (Andrade 2022). By that theory, no drug can be shown to have dangerous side effects, because the initial condition that caused a prescription to be prepared can be blamed.
A Cochrane review of randomized control trials showed that although the benefits of SSRIs were small, “Based on 17 trials (3229 participants in total), there was evidence of an increased risk (64%) of suicide-related outcomes for those on antidepressants compared with those given placebo” (Hetrick et al, 2012), even though “The trials excluded young people at high risk of suicide and many co-morbid conditions and the participants are likely to be less unwell than those seen in clinical practice.” In most studies risk of self-harm or suicide was an exclusion criterion for the study, removing patients from the data (Hetrick et al, 2021), introducing bias and making the suicide and suicide ideation estimates appear lower than for the general population of patients.
Even when participants who are likely to have adverse reactions were excluded from drug trials, and when suicide cases were removed from the data, increases in suicide thoughts and rates prompted the black box warning that was issued by US FDA in 2004 for SSRI antidepressants (Sparks and Duncan 2013). In a study in British Columbia, Schneeweiss et al. 2010 found that “equal event rates among antidepressant agents supports the decision of the Food and Drug Administration to include all antidepressants in the black box warning regarding potentially increased suicidality risk for children and adolescents beginning use of antidepressants.”
FDA noted that the use of antidepressants doubles the risk of harm from suicide or violence (Gøtzsche and Healy 2022), especially for children and adolescents. Suicidal and severely depressed patients were excluded from the randomized-control trials used in the meta-analyses on which the current black box warning is based (McCain 2009). Again, even so, there was cause for concern and vigilance. Healy and Whitaker (2003) noted that randomized control trials revealed an excess of suicidal acts of patients on SSRIs, compared to placebo, with an OR of 2.4 (1.6-3.7, 95% CI). (The odds ratio, OR, is a measure of association in a case-control study; it is the ratio of the odds of an outcome in the one group compared to the odds of the outcome in the other group; it shows how much higher the odds are in the treated or exposed group, compared to the untreated group.)
Some Canadian physicians and clinical pharmacologists have questioned the use of SSRIs in children, although it has become frequent, and the risk-benefit ratio has been questioned. For example, reporters McLean and Bruser (2012) noted in an Ontario survey summary that
“Australian child psychiatrist Jon Jureidini, who has extensively researched Paxil's safety and effectiveness in youth, said, ‘none of the antidepressant trials in children show any clinical advantage of the drug over a placebo. The ones that claim to have (shown such an advantage) have all got flaws in them, either scientific or in the way that they're presented. That means we have no evidence at all to support the use of antidepressants in children.’ "
The article by McLean and Bruser (2012) notes that “British Columbia’s government has issued guidelines for physicians diagnosing and treating children with depression. Doctors are directed to try ‘basic interventions’ and therapy before resorting to prescribing pills.”
The subject has been of interest to questions of legal decisions as well. For example, in a review for the Dalhousie Journal of Legal Studies, Winton (2011) concludes
“Until there is more concrete and independently verified research that demonstrates the short-term and long-term consequences of SSRI use in children and adolescents, physicians should err on the side of caution and simply not prescribe these medications to children and young adolescents. While SSRIs can undoubtedly be ‘miracle drugs’ for some older adolescents, the risk to the vast majority of others does not outweigh the benefits. Unfortunately, for many, the cure is worse than the disease.”
The association between SSRI use and suicide thoughts has been demonstrated repeatedly, and it is also true for realized violent suicide. Based on analysis of data from the Treatment of Adolescent Depression Study (TADS), Hogberg at al. (2015) stated
“We conclude that a major, albeit underreported, finding in the TADS was the significant increase of suicidal events in the adolescents on antidepressant medication in comparison to the group on placebo medication”, and “TADS showed there was a significant increase in suicidal events with fluoxetine, that the risk remained high during the entire treatment period, that the increased suicidality was associated with higher intake scores in self-evaluated depression, and that there were no identified clinical signs indicating the risk for a suicidal event.”
The TADS suicide risk was higher than first indicated (Hogberg et al. 2015). TADS has a history of hidden suicide data that
“has been used to justify the prescribing of Prozac—and really, by extension—other SSRIs to children and adolescents. The TADS researchers reported that the drug treatment was effective and didn’t increase the risk for suicidal events, as compared to placebo. Adding CBT to medication ‘enhances the safety of medication,’ the TADS researchers wrote. All the while, the real suicide data was being hidden. The TADS investigators weren’t disclosing the number of suicide attempts, and they weren’t reporting that all but one of the suicide attempts were in fluoxetine-treated youth. Instead, they made it appear that a similar number of suicidal events had been seen in the placebo group.... the risk of suicide, during the followup phase, was found only in fluoxetine-exposed patients. There were no suicidal events in the CBT-alone group who didn’t take fluoxetine during this period. However, some of the patients in the CBT-alone group were in fact exposed to fluoxetine during the 12-week-to-36-week period (we don’t know how many), and there were two suicidal attempts in those fluoxetine-exposed patients. Here is the bottom line: at the end of 36 weeks, of the 12 suicide attempts in the three groups, 11 were by youth taking fluoxetine.” (Whitaker 2012, “The real suicide data from the TADS study comes to light”; report discussing Hogberg et al. 2015).
Björkenstam et al. (2013) reported the odds ratio (OR) for suicide after initiation of prescribed SSRI of 4.3 (3.0-6.1, 95% CI), in assessment of 4,168 suicides (men; age 13 and up; for women OR values were a bit lower). The increased rates of suicide associated with SSRI antidepressant use are evident in case-control studies, observational studies, and randomized control trials, mainly for adolescents but also for adults in some studies. In a systematic review of observational studies, Barbui et al. (2009) concluded the risk was real but manageable with close monitoring, saying “Among adolescents, use of SSRIs may increase suicidality... Data from observational studies should reassure doctors that prescribing SSRIs to patients with major depression is safe. However, children and adolescents should be followed very closely because of the possibility of increased of risk suicidal thoughts and suicide.”
A world expert in this topic, Hengartner (2017) highlighted some causes for concern in research methodology and bias, and has extensively reviewed and analyzed the evidence of efficacy and suicide rates. “The strong reliance on industry-funded research results in an uncritical approval of antidepressants. Due to several flaws such as publication and reporting bias, unblinding of outcome assessors, concealment and re-coding of serious adverse events, the efficacy of antidepressants is systematically overestimated and harm is systematically underestimated. I therefore conclude that antidepressants are largely ineffective and potentially harmful.”
In discussing a range of studies, Hengartner (2020) notes that “although antidepressant use in children and adolescents has increased substantially over the last 10-15 years, convincing evidence that the benefits outweigh the risks is lacking and treatment emergent suicide remains a major concern.”
SSRI data analysis expert Martin Plöderl summarized it (pers. comm.) and reiterated “Antidepressants are hardly efficacious in children and adolescents, again confirmed by ... meta-analysis.” Hengartner et al., including data analyst Martin Plöderl (2021), found that even for adults, taking antidepressants is associated with an increased suicide rate (RR=1.29, 1.06–1.57; Relative Risk is the ratio of the probability of an outcome in a treatment group to the probability of the outcome in an untreated group). Data from FDA and the Expert Working Group on the Safety of Selective Serotonin Reuptake Antidepressants (2004) indicate that antidepressants pose a risk of suicide in all age groups (Healy 2009), “FDA analysis of the data confirmed a doubling of the risk of suicidal behaviours on active treatment, compared with placebo”.
The long history of antidepressant development, applications for adolescents, and clinical studies are summarized by Healy (2004), Healy et al. (2020), Whitaker (2015), and in a new book by Michael Hengartner, "Evidence-biased Antidepressant Prescription.
Overmedicalisation, Flawed Research, and Conflicts of Interest" (2022), which reviews the evidence and concludes that the affect of SSRI antidepressants (and some new-generation medications) on suicide ideation and suicide fatalities is less clear in adults, but very clear and well known for adolescents. These results and the proven foundation of the black box warning underscore the seriousness of the requirement for monitoring and support by those around adolescents who are prescribed medications like fluoxetine.
Some researchers have examined increases or decreases in use of antidepressants, and numbers of suicides. Whitely et al. (2020) concluded the results “do not support claims that increased antidepressant use reduces youth suicide risk. They are more consistent with the FDA warning and the hypothesis that antidepressant use increases the risk of suicide and self-harm by young people. The trend over time was examined by Plöderl and Hengartner (2021), who found “there is no detectable change of trend in adolescent or young adult suicide rates in line with a detrimental effect of the FDA black box warnings on treatment-emergent suicidality.” As Hengartner (2020) states in his summary of multiple studies, various ecological studies (general correlations, as opposed to controlled or detailed studies) were cited misleadingly as evidence that increased antidepressant use reduces youth suicide risk. Contrary to these claims, studies in Australia Whitely et al. (2020), and in other nations (Amendola et al. 2020) both antidepressant use and suicide rates increased substantially from 2008 to 2018. Whitely et al. (2020) conclude “... results do not support claims that increased antidepressant use reduces youth suicide risk. They are more consistent with the FDA warning and the hypothesis that antidepressant use increases the risk of suicide and self-harm by young people.”
Despite the lack of evidence of a chemical imbalance or serotonin level that causes depression, serotonin does have an impact on brain chemistry and behaviour, showing monitoring is uniformly indicated as being required. This is not new; Reeves and Ladner (2010) say “Evidence suggests that antidepressant treatment may in some cases result in worsening depression and increased risk of suicidality in pediatric and adolescent patients. The United States Food and Drug Administration requires that antidepressants carry a black box warning regarding such a risk in patients up to age 24. ... Close monitoring and a follow-up care should be provided for patients after initiation of a new antidepressant.”
Antidepressants should not be the first choice for young people. Sparks and Duncan (2013) note “The extant literature reviewed herein convincingly suggests that first-line prescription of antidepressants for the pediatric population is not advisable. There is justification, however, for supportive monitoring and watchful waiting without formal intervention in less serious presentations... For now, pediatric antidepressant prescription belongs ‘inside the box.’ ... The black box and international warnings on pediatric use of antidepressants are warranted. Wider availability of psychosocial options for depressed youth is recommended.”
Nassir Ghaemi, Professor of Psychiatry at Tufts Medical Center in Boston, says (2008) “The widely held clinical view of antidepressants as highly effective and specific for the treatment of all types of depressive disorders is exaggerated. This sobering conclusion is supported by recent findings” in NIMH-funded studies. In a 2013 summary, he points out that sadness, even when severe, is caused by losses and distressing circumstances, and antidepressants do not treat any underlying disease or cause of depression.
“The party line is that once sadness crosses arbitrary and vaguely defined thresholds of severity, frequency, duration, and impact, it ceases to be ordinary sadness, resulting from loss or adverse circumstances, and becomes, by some miracle only understood by psychiatrists, a neurobiological illness — a real illness just like diabetes, that needs to be ‘treated’ with neurotoxic chemicals and/or neuro-destructive electric shocks.” - Nassir Ghaemi.
The duty to warn is clear and crucial when prescribing fluoxetine. This must include information provided to and the involvement of the parent or guardian the patient lives with. The increased risks are very real, and continue over months.
Spielmans et al. (2020) emphatically concludes ”the Black Box warning is firmly rooted in solid data whereas attempts to claim the warning has caused harm are based on quite weak evidence.”
and
“...recent data suggests that increasing antidepressant prescriptions are related to more youth suicide attempts and more completed suicides among American children and adolescents. We also note that case-control studies show increased risk of suicide attempts and suicide among youth taking antidepressants, even after controlling for some relevant confounds. As clinical trials have the greatest ability to control relevant confounds, it is important to remember such trials demonstrated increased risk of suicidality adverse events among youth taking antidepressants.... When a clear body of evidence points to increased treatment-linked risk, patients and healthcare providers should be made aware of these risks. To suggest otherwise both breaches the ancient injunction of primum non nocere (first, do no harm) and is not aligned with the practice of evidence-based medicine.”
Spielmans and Perry (2021) point out that not only do the time trends and correlations fails to show that antidepressants reduce suicide, “there are better ways to demonstrate whether a drug causes suicidality, such as the placebo‐controlled trials that originally led to the FDA warning. In sum, the evidence does not support [the] contention that regulatory warnings led to decreased treatment, which then led to increased suicides.”
Black Box warning
The current Prozac (fluoxetine) label warning states: WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1).
Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1).
The general conclusions of carefully summarized and analyzed studies indicate that the increased risk of suicide is real, and the way to manage it is close monitoring and family involvement, particularly at times of dosage changes, as is noted in bold on the fluoxetine (Prozac) label:
“All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.”
It is also a label requirement that this is particularly true of patients thought to fit a diagnosis of Major Depressive Disorder, as adults and adolescents are sometimes diagnosed:
“Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers.”
Information from the pharmacy resource:
“RxTx, formerly known as e-Therapeutics, is the most comprehensive Canadian solution to drug information and therapeutics. The Canadian Pharmacists Association (CPhA) provides two main sources of information; drug information through the well-known Compendium of Pharmaceuticals and Specialties (CPS), and therapeutics through the Compendium of Therapeutic Choices (CTC) and the Compendium for Minor Ailments (CTMA).”
Pediatrics (<18 years of age). PROZAC is not indicated for use in patients below the age of 18 years. See Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; see also Adverse Reactions, Potential for Effects on Growth in Pediatric Patients.
Pediatrics. Though not Health Canada-approved for use in children <18 years of age, SSRIs are used off-label in the management of psychiatric conditions in children, particularly severe, functionally impairing episodes of depression or anxiety. Because of the risk of adverse reactions leading to self-harm or harm to others, close monitoring is important, at the beginning of therapy and throughout (see Warnings and Precautions). Some experts recommend increasing the dosage at longer intervals (2–4 weeks) to decrease risk of behavioural activation, which lowers risk for self-harm and harm to others. Health Canada advises against the use of paroxetine for depression in children <18 years of age.
Product information, from Health Canada:
"Pediatrics (< 18 years of age): ODAN-FLUOXETINE is not indicated for use in patients below the age of 18 years. See WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioural and Emotional Changes, including Self-Harm. See also ADVERSE REACTIONS, Potential for Effects on Growth in Pediatric Patients."
“As with other drugs with similar pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviors have been reported during fluoxetine therapy or early after treatment discontinuation. Page 11 of 50 Although a causal role for fluoxetine in inducing such events has not been established, an FDA analysis from pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or suicidal behaviors in pediatric and young adult (< 25 years of age) patients compared to placebo.
Close supervision of high-risk patients should accompany drug therapy and consideration should be given to the possible need for hospitalization. Physicians should encourage patients of all ages to report any new or worsened distressing thoughts or feelings occurring at any time. In order to minimize the opportunity for overdosage, prescriptions for fluoxetine should be written for the smallest quantity of drug consistent with good patient management. All recommendations from health departments, clinics, suicide prevention groups, instructions for use, etc. indicate the importance of monitoring and family involvement.“
Antidepressants for children and teens. By Mayo Clinic staff
“The FDA advises that doctors prescribe the smallest quantity of pills possible to help reduce the risk of deliberate or accidental overdose. Locking up all pills in the home is one measure families can take to reduce the risk of suicide. Careful monitoring by parents, caregivers and health care professionals is important for any child or teenager taking an antidepressant for depression or any other condition.
The highest risk of suicidal thinking and behavior occurs:
During the first few months of treatment with an antidepressant
When the dosage is increased or decreased
Parents and caregivers should closely observe the child on a daily basis during these transition periods and watch for worrisome changes for the whole time the child takes antidepressants.
The FDA also recommends that your child receive close monitoring by a health care professional during the first few months of treatment, and ongoing monitoring throughout treatment. Frequency of contact with doctors or mental health professionals depends on your child's needs. Make sure you stick to your child's recommended appointment schedule.
Many types of psychotherapy may be helpful, but cognitive behavioral therapy and interpersonal therapy have been scientifically studied and shown to be effective for treating depression.
Cognitive behavioral therapy. In cognitive behavioral therapy, a mental health professional can help your child improve coping skills, communication and problem-solving skills. Your child can also learn how to become aware of harmful ideas and behaviors, replace them with positive approaches, and manage emotions.
Interpersonal therapy. With a focus on relationships, this therapy may help your teenager adapt to changes in current relationships and develop new ones.”
Literature cited
Acker J, Warner L. 2020. Let’s talk about depression: social workers’ use of chemical imbalance explanations. Social Work in Mental Health 18(3):237–256.
Amendola S, Plöderl M, Hengartner M. 2020. Did the introduction and increased prescribing of antidepressants lead to changes in long-term trends of suicide rates? The European Journal of Public Health 31(2):291–297.
Andrade C. 2022. A primer on how to critically read an observational study on adverse medical uutcomes associated with long-term antidepressant drug use. Journal of Clinical Psychiatry 83(6):22f14733.
Ang B, Horowitz M, Moncrieff, J. Is the chemical imbalance an ‘urban legend’? An exploration of the status of the serotonin theory of depression in the academic literature. SSM - Mental Health. 2:100098, 1-9.
Barbui C, Esposito E, Cipriani A. 2009. Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies. Canadian Medical Association Journal 180(3):291-297.
Björkenstam C, Möller J, Ringbäck G, Salmi P, Hallqvist J, Ljung R. 2013. An association between initiation of selective serotonin reuptake inhibitors and suicide - a nationwide register-based case-crossover study. PLoS One 8:1–6.
Bond A. 1998. Drug-induced behavioural disinhibition. CNS Drugs 9:41-57.
Colon, I, Kroin J, Kaushal S, Khan S, Villalba C. 2022. Increased readmission rates in younger male patients due to suicidal risk in newly diagnosed depressive disorders after initiation of serotonin reuptake inhibitors. Cureus 14(11):e31987.
Creaney W, Murray I, Healy D. 1991. Antidepressant induced suicidal ideation. Human Psychopharmacology 6:329-332.
Ghaemi SN. 2008. Why antidepressants are not antidepressants: STEP-BD, STAR*D, and the return of neurotic depression. Bipolar Disorders 10:957–968.
Gøtzsche P, Healy D. 2022. Restoring the two pivotal fluoxetine trials in children and adolescents with depression. International Journal of Risk & Safety in Medicine. 33(4):385-408.
Healy D. 2000. Emergence of antidepressant induced suicidality. Primary Care Psychiatry 6(1):23–28.
Healy D. 2004. Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression. New York: New York University Press.
Healy D. 2009. Are selective serotonin reuptake inhibitors a risk factor for adolescent suicide? Canadian Journal of Psychiatry 54:69-71.
Healy D, Le Noury J, Wood J. 2020. Children of the Cure: Missing Data, Lost Lives and Antidepressants. Samizdat Health Writer’s Cooperative Inc.
Healy D, Aldred G. 2005. Antidepressant drug use & the risk of suicide. International Review of Psychiatry 17(3):163–172.
Healy D, Whitaker C. 2003 Antidepressants and suicide: risk–benefit conundrums. Journal of Psychiatry & Neuroscience 28(5):331-337.
Hengartner M. 2017. Methodological flaws, conflicts of interest, and scientific fallacies: implications for the evaluation of antidepressants’ efficacy and harm. Frontiers in Psychiatry. 8:275.
Hengartner M, Plöder M. 2018. Statistically significant antidepressant-placebo differences on subjective symptom-rating scales do not prove that the drugs work: effect size and method bias matter! (Project: Benefits and harms of psychopharmacological drugs). Frontiers in Psychiatry 9:517.
Hengartner M. 2020. Evidence-biased Antidepressant Prescription. Palgrave Macmillan.
Hengartner M. 2020. How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding. Therapeutic Advances in Psychopharmacology 10:2045125320921694.
Hengartner M, Amendola S, Kaminski J, Kindler S, Bschor T, Plöderl M. 2021. Suicide risk with selective serotonin reuptake inhibitors and other new-generation antidepressants in adults: a systematic review and meta-analysis of observational studies. Journal of Epidemiology and Community Health 8;jech-2020-214611.
Hetrick S, McKenzie J, Cox G, Simmons M, Merry S. 2012. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database of Systematic Reviews 11(11):CD004851.
Hetrick S, McKenzie J, Bailey A, Sharma V, Moller C, Badcock P, Cox G, Merry S, Meader N. 2021. New generation antidepressants for depression in children and adolescents: a network meta‐analysis. Cochrane Database of Systematic Reviews 24(5):CD013674.
Hoehn-Saric R, Lipsey J, McLeod D. 1990. Apathy and indifference in patients on fluvoxamine and fluoxetine. Journal of Clinical Psychopharmacology 10(5):343-345.
Högberg G, Antonuccio D, Healy D. 2015. Suicidal risk from TADS study was higher than it first appeared. International Journal of Risk & Safety in Medicine 27:85–91.
Lenzer J. 2006. Manufacturer admits increase in suicidal behaviour in patients taking paroxetine. BMJ (British Medical Journal) 332(7551):1175.
McCain J. 2009. Antidepressants and suicide in adolescents and adults. A public health experiment with unintended consequences? Pharmacy and Therapeutics 34(7):355-378.
McLean J, Bruser D. 2012. Adult antidepressants suspected in suicides of several Canadian kids. Waterloo Region Record, Dec 8 2012: A4. Kitchener ON.
Moncrieff J, Cooper R, Stockmann T, Amendola S, Hengartner M, Horowitz M. 2022. Systematic review. The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry (2022) DOI:10.1038/s41380-022-01661-0
Oswald I, Healy D, Creaney W. 1991. Fluoxetine and suicide. BMJ (British Medical Journal) 303(6809):1058-1059
Pies R. 2019a. Antidepressant discontinuation: a tale of two narratives. Journal of Clinical Psychopharmacology 39(3):185-188.
Pies R. 2019b. Debunking the two chemical imbalance myths, again. Psychiatric Times 36(8).
Pies R. 2022. The myth of the chemical imbalance. RETURN. March 17 2022.
Plöderl M, Hengartner M. 2021 Effect of the FDA black box suicidality warnings for antidepressants on suicide rates in the USA: signal or noise? Crisis: The Journal of Crisis Intervention and Suicide Prevention. DOI: 10.1027/0227-5910/a000843.
Reeves R, Ladner M. 2010. REVIEW. Antidepressant-induced suicidality: an update. CNS Neuroscience & Therapeutics 16:227–234.
Ide S. 2021. Considering over 30000 suicides in Japan. The Medical Research Information Center Global. Dec 29 2021.
Settle E, Settle G. 1984. Case of mania associated with fluoxetine. American Journal of Psychiatry 141:280-281.
Sparks J, Duncan B. 2013 Outside the black box: re-assessing pediatric antidepressant prescription. Journal of the Canadian Academy of Child and Adolescent Psychiatry 22(3):240-246.
Spielmans G, Parry P. 2021. Black box warning did not cause increased suicides. Psychiatric Research and Clinical Practice 3:97.
Spielmans G, Spence-Sing T, Parry P. 2020. Duty to Warn: antidepressant black box suicidality warning is empirically justified. Frontiers in Psychiatry 11:1-16.
Stone M, Yaseen Z, Miller B, Richardville K, Kalaria S, Kirsch I. 2022. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ 378:e067606.
Teicher M, Glod C, Cole J. 1990. Emergence of intense suicidal preoccupation during fluoxetine treatment. American Journal of Psychiatry 147:207-210.
Whitaker R. 2015. Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America. Broadway Books, New York.
Whitely M, Raven M, Jureidini J. 2020. Antidepressant prescribing and suicide/self-harm by young Australians: regulatory warnings, contradictory advice, and long-term trends. Frontiers in Psychiatry 11:1-14.
Winton K. 2011. Risk v benefits: the use of selective serotonin reuptake inhibitors in children. Dalhousie Journal of Legal Studies. 20(6):128-150.
January 21, 2022. University of Lethbridge. Dexter had just been accepted as a student, although he was still in grade 10.
