Mad in America

This page is about antidepressants as a treatment for depression. It provides a review of the evidence for their short-term use, their adverse effects, and their impact on long-term outcomes. The primary purpose of this review is to detail the research that tells of their long-term effects.

In addition, there are these resources on Mad in America for researching antidepressants:

• • • Our archive of Science News can be searched for articles on antidepressants.
    • Information about antidepressant withdrawal and tapering can be found here.
    • Our MIA Reports provide in-depth journalistic articles on antipsychotics. In particular, see “Do Antidepressants Work? A People’s Review of the Evidence.”  

Evidence for Short-term Use

There has been a great deal of debate about the short-term efficacy of antidepressants as a treatment for depression. There are two parts to this debate. The first is that the evidence comes from industry-funded randomized clinical trials, which are understood to be biased in favor of the drug in several ways.

Bias by design: In the short-term studies, depressed patients who have volunteered for the study are abruptly withdrawn from whatever antidepressant they may have been on, and after a few days they are either randomized to the antidepressant or to placebo. Thus, the placebo group is composed of patients who may be experiencing withdrawal symptoms, which could be expected to negatively impact their outcomes.

Unrepresentative patients: The studies are conducted in a small subset of patients who could be expected to best respond to the drug. Those who are suicidal or co-morbid for other conditions are excluded from such studies.

Industry bias: The pharmaceutical companies funding the studies may spin their results, hide adverse events, and only publish studies with positive results. This leads to a bias in the literature in favor of antidepressants.

The second aspect of the debate is whether these industry-funded trials provide evidence that these drugs provide a meaningful benefit over placebo in reducing depressive symptoms over the short term. The industry-funded trials measure the reduction of symptoms using the Hamilton Rating Scale of Depression (HAM-D). The National Institute of Clinical Excellence in the United Kingdom has stated that there needs to be at least a 3-point difference on this scale, between the antidepressant and placebo groups, for it to be clinically significant. Meta-analyses of the industry-funded trials have found that the difference in symptom reduction between the two groups is a little less than two points. While that difference may be statistically significant, it isn’t a difference that rises to the level of clinical significance. Kirsch and others have calculated “effect sizes” of around .30 for antidepressants based on symptom scores. As is shown by the graph below, which depicts the spectrum of outcomes for two groups with an effect-size difference of .30, this means that there is an 88% overlap in the distribution of outcomes for the drug-treated and placebo patients.

Given this effect size, researchers have determined that you need to treat 8 people with an antidepressant to produce one additional person who benefits from the treatment. This is called an NNT of 8. Seven out of eight people treated with an antidepressant will be exposed to the adverse effects of the drug without gaining any additional benefits beyond placebo in the reduction of depressive symptoms.

Outcomes in real-world patients

Response rates to antidepressants are much lower in studies that enroll real-world patients. In a study of 118 “real-world” outpatients, only 19% of the patients had responded to an antidepressant after three months, which is a much lower response rate than is usually seen in the industry-funded trials. The NIMH funded a large study, known as the STAR*D study, to assess the effectiveness of antidepressants in real-world patients, and even though patients were given up to four courses of treatment with different antidepressants, only 38% ever responded to the treatment.  

Adverse Effects

SSRIs and SNRIs may cause nausea, vomiting, insomnia, sedation, constipation, fainting, sweating, headaches, palpitations, rashes, weight gain, blurred vision, tremors, shivering, high fever, seizures, abnormal bleeding, and stroke. Emotional and psychiatric side effects include depersonalization, derealization, confusion, mania, and psychosis.  In teenagers and adults, sexual dysfunction is common, and a significant percentage of youth may experience a severe inner agitation called akathisia, which is associated with an increased risk of violence and suicide. Withdrawal symptoms can be severe. Longer-term use may lead to cognitive decline and to persistent sexual dysfunction, even after withdrawal from the drug.  

Long-term Outcomes

An understanding of the impact of antidepressants over the long-term can be pieced together from a historical review of the scientific literature, which tells of how antidepressants, over the long-term, increase the risk that a person will become chronically depressed and functionally impaired.

 

A. The Natural Course of Depression

Prior to the widespread use of antidepressants, the National Institute of Mental Health told the public that people regularly recovered from a depressive episode, and often never experienced a second episode. As the NIMH’s Jonathan Cole wrote in 1964: “Depression is, on the whole, one of the psychiatric conditions with the best prognosis for eventual recovery, with or without treatment.” Even in studies of hospitalized patients, 85% could be expected to recover within a year (or even faster). Most depressive episodes, explained Dean Schuyler, head of the depression section at the NIMH, in 1974, “will run their course and terminate with virtually complete recovery without specific intervention.”

 

B. The Chronicity Problem Appears

However, once psychiatrists began treating their depressed patients with antidepressants, several observed that many of their patients, once they got better and stopped taking the drugs, became depressed again. While the drugs might help people over the short-term, it appeared their use was causing a “chronification” of the disease.

1. Recurrent vital depressions. Van Scheyen, J. Psychiatry, Neurologia, Neurochirugia 76 (1973):93-112. After reviewing the literature and conducting his own study, Dutch investigator J.D. Van Scheyen concluded that “more systematic long-term antidepressant medication, with or without ECT, exerts a paradoxical effect on the recurrent nature of the vital depression. In other words, this therapeutic approach was associated with an increase in recurrence rate and a decrease in cycle duration.”  

C. Researchers Report Relapse is Common After Exposure to an Antidepressant

During the 1970s and 1980s, the NIMH and other groups reported that patients withdrawn from antidepressants “relapsed” at higher rates than in pre-antidepressant era. More recent studies have shown that these relapse rates are much higher than for patients treated with placebo.

2. An evaluation of continuation therapy with tricyclic antidepressants in depressive illness. Mindham, R. Psychological Medicine 3 (1973):5-17. British researchers found that 50% of drug-withdrawn patients relapsed within six months.

3. Maintenance therapy with amitriptyline. Stein, M. American Journal of Psychiatry 137 (1980):370-1. Investigators at the University of Pennsylvania reported that 69% of patients withdrawn from an antidepressant relapsed within six months. There was “rapid clinical deterioration in most of the patients.”

4. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Prien, R. Archives of General Psychiatry 41 (1984):1096-1104. Robert Prien at the NIMH reported that 71% of depressed patients relapsed within 18 months of drug withdrawal.

5. Course of depressive symptoms over followup. Shea, M. Archives of General Psychiatry 49 (1992):782-87. In an 18-month NIMH study that compared four types of treatment (two forms of psychotherapy, an antidepressant, and placebo), the group that was initially treated with the antidepressant had the lowest stay-well rate by the end of the study.

6. Discontinuing antidepressant treatment in major depression. Viguera, A. Harvard Review of Psychiatry 5 (1998):293-305. In a meta-analysis of the relapse literature, Harvard researchers concluded that at least 50% of drug-withdrawn patients relapsed within 14 months.  

D. Medicated Depression Runs a Chronic Long-Term Course, But Unmedicated Depression Doesn’t

In the pre-antidepressant era, epidemiological studies found that patients regularly recovered from a depressive episode and often stayed well for years (or simply suffered a single episode of depression.) Long-term studies conducted in the 1990s and early 2000s found that medicated depression runs a much more chronic course, with only a small percentage of people enjoying a sustained remission. In contrast, a one-year study of unmedicated depression conducted in the 1990s reported a one-year recovery rate of 85%, similar to the recovery rate in the pre-antidepressant era.

7. Does incomplete recovery from first lifetime major depressive episode herald a chronic course of illness? Judd, L. American Journal of Psychiatry 157 (2000):1501-4. Two-thirds of all unipolar depressed patients either do not respond to initial treatment with an antidepressant or only partially respond, and these patients fare poorly over the long-term. NIMH-funded investigators reported in this study that “resolution of major depressive episode with residual subthreshold depressive symptoms, even the first lifetime episode, appears to be the first step of a more severe, relapsing, and chronic future course.”

8. One-year clinical outcomes of depressed public sector outpatients. Rush, J. Biological Psychiatry 56 (2004):46-53. Psychiatrists at Texas Southwestern Medical Center in Dallas noted that most clinical studies “cherry-pick” patients most likely to respond well to an antidepressant. In this long-term study of “real-world” patients, only about 13% of the patients stayed better for any length of time. These “findings reveal remarkably low response and remission rates,” the investigators concluded.

9. Efficacy and Effectiveness of Antidepressants. Pigott, H. Psychotherapy and Psychosomatics 79 (2010):267-279. In a large NIMH trial of 4,041 “real-world” outpatients, known as the STAR*D study, only 108 patients remitted and stayed well and in the trial during the one-year followup. This is a stay-well rate of 3%.

10. The naturalistic course of major depression in the absence of somatic therapy. Posternak, M. Journal of Nervous and Mental Disease 194 (2006):324-9. In an NIMH study of “untreated depression,” 23% of the non-medicated patients recovered in one month; 67% in six months; and 85% within a year. “If as many as 85% of depressed individuals who go without somatic treatments spontaneously recover within one year, it would be extremely difficult for any intervention to demonstrate a superior result to this,” the investigators wrote.  

E. Researchers Provide a Biological Explanation for Why Drugs May Worsen Long-term Outcomes In the 1990s and early 2000s, an Italian psychiatrist, Giovanni Fava, wrote papers on how it appeared that antidepressants increased the likelihood that a person suffering a depressive episode would become chronically ill. He and others hypothesized that antidepressants induced an “oppositional tolerance,” which could lead to a chronic depressive state called tardive dysphoria.

11. Do antidepressant and antianxiety drugs increase chronicity in affective disorders? Fava, G. Psychotherapy and Psychosomatics 61 (1994):125-31. “The time has come for debating and initiating research into the likelihood that psychotropic drugs actually worsen, at least in some cases, the progression of the illness which they are supposed to treat,” Fava wrote in this paper.

12. Holding on, depression, sensitization by antidepressant drugs, and the prodigal experts. Fava, G. Psychotherapy and Psychosomatics 64 (1995):57-61. Antidepressant drugs in depression might be beneficial in the short term, but worsen the progression of the disease in the long term, by increasing the patient’s biochemical vulnerability to depression.

13. Risks and implications of interrupting maintenance psychotropic drug therapy. Baldessarini, R. Psychotherapy and Psychosomatics 63 (1995):137-41. Harvard psychiatrist Ross Baldessarini writes: Fava’s “question and the several related matters . . . are not pleasant to contemplate, but they now require open-minded and serious clinical and research consideration.”

14. Potential sensitising effects of antidepressant drugs on depression. Fava, G. CNS Drugs 12 (1999):247-56. Use of antidepressant drugs may propel the illness to a more malignant and treatment-unresponsive course.

15. Can long-term antidepressant use be depressogenic? El-Mallakh, R. Journal of Clinical Psychiatry 60 (1999):263. “Long-term antidepressant use may be depressogenic . . . it is possible that antidepressant agents modify the hardwiring of neuronal synapses (which) not only render antidepressants ineffective but also induce a resident, refractory depressive state.”

16. Can long-term treatment with antidepressant drugs worsen the course of depression? Fava, G. Journal of Clinical Psychiatry 64 (2003):123-33. In order to cope with the antidepressant’ perturbation of neurotransmitter activity, the brain undergoes compensatory adaptations, and “when drug treatment ends, these (compensatory) process may operate unopposed, resulting in appearance of withdrawal symptoms and increased vulnerability to relapse,” Fava said.

17. Tardive Dysphoria: The Role of Long-term Antidepressant Use in Inducing Chronic Depression. El-Mallakh, R. Medical Hypotheses 76 (2011):769-773. Antidepressants “may induce processes that are the opposite of what the medication originally produced,” and this may “cause a worsening of the illness, continue for a period of time after discontinuation of the medication, and may not be reversible.” The researcher writes: “A chronic and treatment-resistant depressive state is proposed to occur in individuals who are exposed to potent antagonists of serotonin reuptake pumps for prolonged time periods. Due to the delay in the onset of this chronic depressive state, it is labeled tardive dysphoria.”

F. Unmedicated Depression vs. Medicated Depression Today In the past 25 years, researchers in Europe, Canada and the United States have conducted a variety of “naturalistic” studies that have regularly shown that, over the long-term, medicated patients are more likely to be depressed and functionally impaired.

18. Characteristics and significance of untreated major depressive disorder. Coryell, W. American Journal of Psychiatry 152 (1995):1124-9. NIMH-funded investigators tracked the outcomes of medicated and unmedicated depressed people over a period of six years; those who were “treated” for the illness were three times more likely than the untreated group to suffer a “cessation” of their “principal social role” and nearly seven times more likely to become “incapacitated.” The NIMH researchers wrote: “The untreated individuals described here had milder and shorter-lived illness (than those who were treated), and, despite the absence of treatment, did not show significant changes in socioeconomic status in the long term.”

19. Outcome of anxiety and depressive disorders in primary care. Ronalds, C. British Journal of Psychiatry 171 (1997):427-3. In a British study of 148 depressed patient, the never-medicated group saw their symptoms decrease by 62% in six months, whereas the drug-treated patients experienced only a 33% reduction in symptoms.

20. The effects of detection and treatment on the outcome of major depression in primary care. Goldberg, D. British Journal of General Practice 48 (1998):1840-4.

In a WHO study of depressed patients in 15 cities around the world, which was designed to assess the merits of screening for the disorder, it found that, at the end of one year, those who weren’t exposed to psychotropic medications enjoyed much better “general health,” their depressive symptoms were much milder, and they were less likely to still be “mentally ill.”

21. Treatment of depression related to recurrence. Weel-Baumgarten, E. Journal of Clinical Pharmacy and Therapeutics 25 (2000):61-6. In a retrospective study of 10-year outcomes, Dutch investigators found that 76% of those not treated with an antidepressant recovered and never relapsed, compared to 50% of those prescribed an antidepressant.

22. Pattern of antidepressant use and duration of depression-related absence from work. Dewa, S. British Journal of Psychiatry 183 (2003):507-13. Canadian investigators identified 1,281 people who went on short-term disability between 1996 and 1998 because they missed ten consecutive days of work due to depression; those who didn’t fill a prescription for an antidepressant returned to work, on average, in 77 days, while the medicated group took 105 days to get back on the job. Only 9% of the unmedicated group went on to long-term disability, compared to 19% of those who took an antidepressant.

23. The impact of antidepressant treatment on population health. Patten, S. Population Health Metrics 2 (2004):9-16. In a five-year study of 9,508 depressed patients in Canada, medicated patients were depressed on average 19 weeks a year, versus 11 weeks for those not taking the drugs. The Canadian investigators concluded that their finds were consistent with Giovanni Fava’s hypothesis that “antidepressant treatment may lead to a deterioration in the long-term course of mood disorders.”

24. Continuing and maintenance use of antidepressants in recurrent depression. Bockting, C. Psychotherapy and Psychosomatics 77 (2008):17-26. Researchers in the Netherlands followed 172 patients for two years after their depression had initially gone into remission, and found that during this follow-up the relapse rate was 60% for those who continuously took an antidepressant, 64% for those who intermittently took one, and 26% for those who didn’t take an antidepressant at all.

25. Impact of duration of antidepressant treatment on the risk of a new sequence of antidepressant treatment. Verdoux, H. Pharmopsychiatry 44 (2011):96-101. French researchers, in a study of 35,000 first-episode patients, found that the longer patients were treated with an antidepressant before withdrawing it, the higher the rate of relapse. Those who were exposed to an antidepressant for longer than six months had more than twice the risk of relapse than those exposed for less than one month.

26. Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression. Andrews, P. Frontiers in Psychology 2 (2011):159. In a meta-analysis of 46 studies, researchers found that the relapse rate for placebo responders during a followup period was 25%, compared to 45% of drug responders who were then withdrawn from the drug.

27. Poorer long-term outcomes among persons with major depressive disorder treated with medication. Vittengl, J. Psychotherapy and Psychosomatics 86 (2017):302-304. An analysis of the outcomes of 3,294 people who were diagnosed with depression and followed for nine years revealed that those who took antidepressants during that period had more severe symptoms at the end of nine years than those who didn’t take such medication. The difference in outcomes could not be explained by any difference in initial severity of depression.

28. Antidepressant use prospectively relates to a poorer long-term outcome of depression: Results from a prospective community cohort study over 30 years. Hengartner, M. Psychotherapy and Psychosomatics 28 (2018):181-183. A prospective study of 521 depressed patients in Switzerland, who were followed from when they were 20 years old until they were 50 years old, found that taking an antidepressant at some point during that period was associated with worse outcomes at the end of the study, even when controlling for initial symptoms and other factors.

29. Antidepressant Use During Acute Inpatient Care Is Associated With an Increased Risk of Psychiatric Rehospitalisation Over a 12-Month Follow-Up After Discharge. Hengartner M. Frontiers in Psychiatry 10 (2019):79. Swiss investigators, in a study of 90 psychiatric patients discharged from two psychiatric hospitals, found that those treated with an antidepressant while in the hospital were more than three times as likely to be rehospitalized in the following 12 months than those who were not treated with an antidepressant. At the study outset, the antidepressant-user and non-user groups were “matched into pairs” on a variety of clinical outcomes including illness severity, functional deficit, and psychosocial impairment, a design intended to isolate the effects of the antidepressant use.

30. Prior antidepressant treatment trials may predict a greater risk of depressive relapse during antidepressant maintenance therapy. Amsterdam, J. J of Clinical Psychopharmacology 39 (2019):344-350. A study of 148 people with a bipolar II diagnosis who had recovered from a depressive episode found that the “largest predictor of relapse” over the next 50 weeks was whether they had taken an antidepressant before enrolling in the study. Those who had taken an antidepressant were nearly three times more likely to relapse.

G. Disability in the Age of Prozac In the United States and other countries where use of antidepressants has become commonplace, the number of adults on disability due to mood disorders has risen in lockstep with the increase in antidepressant usage.  

G. Summary of Long-term Evidence

The scientific literature tells a story that stretches over the span of fifty years. When the antidepressants are introduced, at least a few psychiatrists worry that the drug treatment is causing a chronification of the disorder. Over the next two decades, researchers find that patients treated with antidepressants are relapsing more frequently than before. Studies in the 1990s and early 2000s do indeed find that the majority of depressed patients do not achieve a sustained recovery. Medicated depression is found to run a more chronic course than it had in the pre-antidepressant era. Numerous studies since 1995 tell of how patients treated with antidepressants are more likely than unmedicated patients to remain symptomatic over longer periods of time. Studies find that antidepressants increase the risk that a person suffering from an episode of depression will become disabled by the disorder. In country after country, the increased prescribing of antidepressants has been accompanied by an increase in disability due to mood disorders.  

Research compiled by Robert Whitaker

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