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.” Given this understanding of the natural course of depression, the NIMH’s experts believed that antidepressants might shorten the time to recovery, but they wouldn’t be able to boost long-term recovery rates. The reason, explained Dean Schuyler, head of the depression section at the NIMH, in 1974, was that most depressive episodes “will run their course and teminate with virtually complete recovery without specific intervention.”


B. The Chronicity Problem Appears

Once psychiatrists began treating their depressed patients with antidepressants, at least a few observed that these patients, once they got better and stopped taking the drugs, regularly became depressed again. While the drugs might help people over the short-term, they were putting them onto a more chronic long-term path.

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 effct 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.” As he noted, other psychiatrists had observed that antidepressants were causing a “chronification” of the disease.


C. The High Relapse Rate After Exposure to an Antidepressant

During the 1970s and 1980s, the NIMH and other groups reported that patients withdrawn from antidepressants “relapsed” at high rates.

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British researchers found that 50% of drug-withdrawn patients relapsed within six months.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Investigators at the University of Pennsylvania reported that 69% of patients withdrawn from an antidepressant relapsed within six months.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, Havard researchers concluded that at least fifty percent of drug-withdrawn patients relapsed within 14 months.

7.  Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression. Andrews, P. Frontiers in Evolutional Psychiatry 2 (2011): 159.

In a meta-analysis of 46 studies, researchers found that the relapse rate for placebo responders during a followup period was 24.7%, compared to 44.6% of drug responders who were then withdrawn from the drug.


D. The Problem of Drug-Induced Chronicity is Discussed

In the 1990s and early 200s, an Italian psychiatrist, Giovanna Fava, repeatedly wrote papers on how it appeared that antidepressants increased the likelihood that a person suffering a depressive episode would become chronically ill. At least a few other prominent experts in the field agreed that psychiatry needed to investigate this problem.

8. 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 intitiating research into the liklihood 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.

9. 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.

10. 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.

11. 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.

12. 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.”

13. 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.

14. Tardive Dysphoria: The Role of Long-term Antidepressant Use in Inducing Chronic Depression. El-Mallkh, 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.”


E. The Transformation of Depression

Rather than confront the possibility that antidepressants were making patients chronically ill, psychiatry–as a field–told a new story about the course of unmedicated depression. Early epidemiological studies showing that patients regularly recovered from a depressive episode and often stayed well must have been “wrong,” they said. Modern research had shown that depression was a chronic illness, which required continual medication. And indeed, studies now showed that patients treated with antidepressants fared quite poorly over the long term, even though they were maintained on the drugs. (The poor outcomes were blamed on the disease, not the drug, however.)

15. 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 sudy 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, relasping, and chronic future course.”

16. 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.

17. 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, only 108 patients remitted and stayed well and in the trial during the one-year followup.


F. Unmedicated Depression vs. Medicated Depression Today

Prior to the widespread use of antidepressants, depressed patients regularly got well, and many never suffered a second bout of major depression. Today, the overwhelming majority of patients diagnosed with major depression and treated with antidepressants suffer recurrent bouts of the illness. But what does unmedicated depression look like today? Does it run a better long-term course than medicated depression? Researchers in Europe, Canada and the United States have conducted a variety of “naturalistic” studies that help answer that question.

18. Outcome of anxiety and depressive disorders in primary care. Ronalds, C. British Journal of Psychiary 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.

19. 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.

20. 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.”

21. The effects of detection and treatment on the outcome of major depressoin 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;” that their depressive symptoms were much milder;” and that they were less likely to still be “mentally ill.”

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 nine percent of the unmedicated group went on to long-term disability, compared to nineteen percent of those who took an antidepressant.

23. 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 socieoeconomic status in the long term.”

24. 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,” twenty-three percent of the non-medicated patients recovered in one month; 67% in six months; and 85% within a year. This modern study showed that the advice given by the NIMH in the late 1960s was correct: Most people struck by a bout of major depression naturally recovered. “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.