Long-term Evidence We Can’t Overlook Anymore: Anti-Depressant Outcomes

The set of studies below have been gathered and shared over recent years by award-winning journalist, Bob Whitaker.  The cumulative findings represented here are both hugely important, and largely not a part of the public mental health conversation we are having today. Given the precious value of each person facing serious mental distress, I dearly hope that can change.

I have interviewed Bob twice and find him a man of both high integrity and great modesty – and give credit for the bulk of what follows to his investigative work. In many cases, I share his own analysis verbatim, with adjustments for brevity. Thanks to Bob for the graphics, statistics and explanations that follow.  [To review more, I highly encourage you to access Bob’s books and many presentations].

To watch Bob’s own presentation of some of these findings, check out the video below: Long-term Anti-depressant Outcome Research

Bob’s own written review can be accessed on page 164-169 in this chapter of his book as well. For those looking for a quick summary of the key studies, I provide summarizes alongside Bob’s own graphs below and a hyperlink to the original study. These 20 studies (representing the full scope of the long-term anti-depressant studies in existence) are organized chronologically from oldest to newest studies:

(1) 1973: A long-term review of 94 depressed patients. [Van Scheyen, J. Recurrent vital depressions. Psychiatry, Neurologia, Neurochirugia 76 (1973):93-112].

J.D. Van Scheyen, a Dutch psychiatrist, concluded from his own original research and a review of the existing literature that that “it was evident, particularly in the female patients, that more systematic long-term antidepressant medication, with or without ECT [electronconvulsive therapy], exerts a paradoxical effect on the recurrent nature of the vital depression. In other words, this therapeutic approach was associated with an increase in recurrent rate and a decrease in cycle duration.”

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

Dr. Scheyen went on to ask, “Should [this increase] be regarded as an untoward long-term side effect of treatment with tricyclic antidepressants?”

Between the 1970’s and early 1980’s, the NIMH and other groups reported on four different occasions that patients withdrawn from antidepressants were showing uniquely high relapse rates:

(2) 1973: Six-month follow-up of 92 depressed patients. [Mindham, R. An evaluation of continuation therapy with tricyclic antidepressants in depressive illness. Psychological Medicine 3 (1973):5-17].

British researchers found that 50% of drug-withdrawn patients relapsed within six months.

(3) 1980: Six-month Follow-up of 55 depressed patients.  [Stein, M. Maintenance therapy with amitriptyline.  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) 1984: Two-year follow-up of 267 depressed patients [Prien, R.  Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders.. 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) 1986: Two-year follow-up of depressed patients [Blackburn, I . M., Eunson, K., St Bishop, S. A two-year naturalistic follow-up of depressed patients treated with cognitive therapy, pharmacotherapy and a combination of both. Journal of Affective Disorders, 10, 67-75].

This research team likewise found that significantly more patients in the group given anti-depressants alone relapsed at both 6 month and 2 year time-points, when compared to psychotherapy in various combinations.

 (6) 1992: 16-Week results compared to 18-month results [Shea, M., Elkin, Itnber, S ., Sotsky, S., Watkins, J., Collins, J., et al. Course of depressive symptoms over followup. Findings from the National Institute of Mental Health Treatment of Depression Research Program. Arch Gen Psychiatry 49 (1992): 782-787].

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 (19%) – and the highest relapse rate (50%). If study dropouts were included in the analysis, then the results for the imipramine patients “look even worse . . . patients receiving the antidepressant were most likely to seek treatment following termination, produced the highest probability of relapse, and exhibited the fewest weeks of reduced or minimal symptoms during the follow-up period.”

(7) 1995: Six-year NIMH follow-up on 547 people diagnosed with depression [Coryell, W., Characteristics and significance of untreated major depressive disorder.  American Journal of Psychiatry 152 (1995):1124-9].

NIMH-funded investigators led by University of Iowa psychiatrist William Coryell 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.” While many of the treated patients saw their economic status markedly decline during the six years, only 17 percent of the unmedicated group saw their incomes drop, and 59 percent saw their incomes rise.  The NIMH researchers noted that overall: “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.”

(8) 1997: Six-month follow-up up of 148 depressed patients. [Ronalds, C.  Outcome of anxiety and depressive disorders in primary care.”  British Journal of Psychiary 171 (1997): 427-33].

In a 1997 study of the outcomes of 148 depressed patients at a large inner-city facility, British scientists reported that ninety-five never-medicated patients saw their symptoms decrease by 62 percent in six months, whereas the fifty-three drug-treated patients experienced only a 33 percent reduction in symptoms.  The medicated patients, they concluded, “continued to have depressive symptoms throughout the six months.”

(9) 1998: Harvard meta-analysis of 27 studies across 3037 depressive patients treated for up to 48 months (6 month average), then followed for up to 66 months (17 month average) [Viguera, A. “Discontinuing antidepressant treatment in major depression.” Harvard Review of Psychiatry 5:293-305].

In a meta-analysis of the relapse literature, Havard researchers concluded that at least fifty percent of all drug-withdrawn patients relapsed within 14 months. They also noted that the longer the patient had been on an antidepressant prior to drug withdrawal, the higher the relapse rate. (In the pre-antidepressant era, this was the relapse rate seen in studies that lasted 15 years or more.)

(10) 1998: Twelve-month World Health Organization follow-up on 740 people screened for depression in 15 cities around the world [D. Goldberg, M. Privett, B. Ustun, G. Simon & M. Linden. The effects of detection and treatment of major depression in primary care: A naturalistic study in 15 cities. British Journal of General Practice 48:1840-44].

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. The hypothesis behind the study was that those treated with antidepressants would have the best long-term outcomes, and those whose depression is not detected and thus don’t receive treatment would fare the worst. The results were the opposite of what they expected. At the end of one year, the subset of 484 people 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.” By comparison, the group that suffered most from “continued depression” were the patients receiving antidepressant treatment.

The lead researcher noted: “Patients not given drugs had milder illnesses but did significantly better than those receiving drugs, both in terms of symptoms lost and their diagnostic status.” This was so “even after adjustment for initial scores on each instrument.” The researchers concluded, the “study does not support the view that failure to recognize depression has serious adverse consequences.”

(11) 1998: One-year follow-up of 100 people [Rost K, Zhang M, Fortney J, et al. (1998) Persistent poor outcomes of undetected major depression in primary care: implications for intervention. General Hospital Psychiatry, 20, 12-20].

Patients in general practice receiving antidepressant treatment as recommended in guidelines had higher rates of relapse than those receiving no therapy.

(12) 2000: Ten-year follow-up of 222 people who had suffered a first episode of depression [E. Weel-Baumgarten, “Treatment of depression related to recurrence,” Journal of Clinical Psychiatry & Therapeutics 25 (2000):61-66].

In a retrospective study tracking 10-year case history outcomes in retrospect, Dutch investigators found that 76% of those not treated with an antidepressant recovered and never relapsed, compared to 50% of those prescribed an antidepressant. The lead researcher wrote, “Even when a diagnosis of Major Depressive Disorder has been made, spontaneous recovery should be considered for a number of cases in general practice and watchful waiting could prove worthwhile.”

(13) 2003: 1281 people assessed for anti-depressants and rates of disability [C Dewa. “Pattern of antidepressant use and duration of depression-related absence from work.” here’s a hard-copy version from the journal) British Journal of Psychiatry 183 (2003):507-13].

In Canada, Carolyn Dewa and her colleagues at the Center for Addiction and Mental Health in Ontario set out to explore the relationship between antidepressants and disability rates.  They first identified 1,281 people who went on short-term disability between 1996 and 1998 because they missed ten consecutive work days due to depression.  The 564 people who opted to not go on antidepressants returned to work, on average, in 77 days – while the medicated group took 105 days to get back on the job, on average.  More important, those who took an antidepressant were more than twice as likely to go on to long-term disability, with only 9 percent of the unmedicated group submitting a request for long-term disability, compared to 19 percent of those who took an antidepressant.  “Does the lack of antidepressant use reflect a resistance to adopting a sick role and consequently a more rapid return to work?” the researcher wondered.

(14) 2004: Five-year follow-up of 9,508 depressed patients [S. Patten, “The Impact of antidepressant treatment on population health.” Population Health Metrics 2: 9].

In a five-year University of Calgary 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. Episodes occurring in antidepressant users lasted longer than those in non-users. The apparent incidence of major depressive episodes among those taking antidepressants was higher than that among respondents not taking antidepressants. The lead author, Scott Patten, wrote that “these findings are consistent with Giovanni Fava’s hypothesis that ‘antidepressant treatment may lead to a deterioration in the long-term course of mood disorders.’”

(15) 2004: One-year NIMH follow-up of 118 people [J. Rush. “One-year clinical outcomes of depressed public sector outpatients,” Biological Psychiatry 56: 46-53].

126 patients were originally treated with antidepressants and given emotional and clinical support “specifically designed to maximize clinical outcomes.” 26% responded to antidepressants (50% reduction in symptoms), with only half of those who responded staying better for a significant period of time. Overall, only 6% remitted and then remained in remission at the end of one year. Lead author John Rush acknowledged, “These findings reveal remarkably low response and remission rates.”

(16) 2006: Up to 15-year NIMH follow-up of 84 unmedicated people facing depression [Posternak, M. “The naturalistic course of major depression in the absence of somatic therapy Journal of Nervous and Mental Disease 194 (2006): 324-349].

Dr. Michael Posternak, a psychiatrist at Brown University wrote that “unfortunately, we have little direct knowledge regarding the untreated course of major depression.” (Much of the existing knowledge for poor long-term outcomes in textbooks told the story of medicated depression). In an NIMH study of “untreated depression,” He and his team identified a subset of 84 people in a larger NIMH study who had relapsed but chosen not to go back on anti-depressants. How did these 84 people fare over the years they were tracked?  Twenty-three percent of the non-medicated patients recovered in one month; 67% in six months; and 85% within a year. Kraepelin, Posternak noted, had said that untreated depressive episodes usually cleared up within six to eight months, and these results provided “perhaps the most methodologically rigorous confirmation of this estimate.” Overall, most people struck by a bout of major depression naturally recovered: “These results suggest that there is a high rate of recovery in individuals not receiving somatic treatment of their depressive illness, particularly in the first 3 months of an episode.” For all 84 subjects who went unmedicated, the “median time to recovery was 13 weeks.” They added: “treatment-seeking behavior is known to be associated with a worse prognosis.” The investigators concluded, “If as many as 85% of depressed individuals who go without somatic [medical] treatments spontaneously recover within one year, it would be extremely difficult for any intervention to demonstrate a superior result to this.”

(17) 2008: Two-year follow-up of 172 patients facing depression [C. Bockting. “Continuation and maintenance use of antidepressants in recurrent depression.” Psychotherapy and Psychosomatics 77 (2008): 17-26].

Lead researcher, C. Bockting, wrote, “Continued antidepressant treatment may oppose the initial acute effects of [the] antidepressant . . . neurobiological mechanism(s) may be involved in increasing vulnerability.”

(18) 2010: Patterns across over 260,000 patients facing depression [MN Community Measures, 2010 Health Care Quality Report]

(19) 2011: Meta-analysis of 46 studies exploring antidepressant discontinuation.  [Andrews, P. Blue Again: Perturbational Effects of Antidepressants Suggest Monoaminergic Homeostasis in Major Depression. Frontiers in Evolutional Psychiatry 2 (2011): 159].

In a meta-analysis of 46 studies looking at discontinuation of anti-depressant medications, 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.

(20) 2012: Comprehensive review of the long-term research on anti-depressants. [P. Andrews: Primum non nocere: An evolutionary analysis of whether antidepressants do more harm than good. Frontiers in Psychology 3 (2012):  1-18].

This comprehensive review of the literature included an original meta-analysis of studies in which anti-depressants are discontinued. The authors found more than twice as much depression relapse on those treated by SSRI anti-depressants long-term, when compared to those receiving placebo (see graph below). Looking across all the long-term evidence, the authors conclude, “it is widely believed that antidepressant medications are both safe and effective; however, this belief was formed in the absence of adequate scientific verification. The weight of current evidence suggests that, in general, antidepressants are neither safe nor effective; they appear to do more harm than good.” The lead researcher, Paul Andrews, wrote, “The more antidepressants perturb monamine levels in the brain, the more the brain appears to push back, which increases the risk of relapse when the drug is discontinued . . . antidepressant use appears to increase [biological] susceptibility to depression.”

As reflected above, this pattern showed up again and again, across multiple converging evidence bases.  Generally speaking, people taking antidepressants long-term don’t fare so well. That’s the simple truth.

 Same patterns with anti-psychotics and anti-anxiety drugs.  This pattern of increasing chronicity associated with long-term treatment is not exclusive to anti-depressants. Other classes of psychiatric meds show the same patterns. For instance, there is extensive evidence that anti-psychotics lead to the same patterns long-term, as evident in this 2016 talk (20:55-29:49): Long-term outcomes from anti-psychotics. For a more detailed summary of the same literature, watch his 2015 talk given to the Council for Evidence-based Psychiatry, starting with 20:56 and ending with 49:25.  Or check out this clip from our own interview with Bob: Takeaways from Long-term Anti-psychotic Outcome Research

For a review of the 50 years of evidence documenting long-term poor outcomes for anti-psychotics, see this full-text review or this summary of the 25 studies involved.

One representative 2007 study is cited for illustration:  [Harrow M. & Jobe, T H. “Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications.” Journal of Nervous and Mental Disease 195 (2007):406-14]. 

Harrow shared other data regarding work history:

Harrow later said about his data, “How unique among medical treatments is it that the apparent efficacy of antipsychotics could diminish over time or become ineffective or harmful? There are many examples for other medications of similar long-term effects, with this often occurring as the body readjusts, biologically, to the medications.”

Biological Explanations for the Long-Term Outcomes of Psychiatric Meds

Stephen Hyman, former director of the NIMH, first raised some of this explanation in 1996, noting that psychiatric medications “create perturbations in neurotransmitter functions.” In response, the brain goes through a series of compensatory adaptations in order “to maintain their equilibrium in the face of alterations in the environment or changes in the internal milieu.” The “chronic administration” of the drugs then cause “substantial and longlasting alterations in neural function.” After a few weeks, the person’s brain is now functioning in a manner that is “qualitatively as well as quantitatively different from the normal state.”[1]

In 2003, Fava added the following: “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” [Can long-term treatment with antidepressant drugs worsen the course of depression? Fava, G. Journal of Clinical Psychiatry 64 (2003):123-33].

There are many studies documenting various brain changes elicited by psychiatric meds.  For instance, in 2004, chronic antidepressant treatment was documented as resulting in a down-regulation of the synaptic function of forebrain 5-HT2 receptors. [Chronic Antidepressant Treatment Alters Serotonergic Regulation of Gaba Transmission In Prefrontal Cortical Pyramidal Neurons, by P. Zhong And Z. Yan, Neuroscience 129 (2004) 65–73].

In studies with rats, long-term treatment with an SSRI led to markedly reduced serotonin in “nine areas of the brain.” As a team led by Dr. El-Mallakh at the University of Louisville found in 2011, treatment with an SSRI leads to a reduced density of receptors for serotonin in the brain. In experiments with animals, such impairments in serotonergic functions are “associated with increased depressive and anxious behaviors.”[2]

 Dr. El.-Mallakh concluded that over time, antidepressants “may induce processes that are the opposite of what the medication originally produced.” “Rather than raise serotonin levels, the drugs over the long-term impair serotonergic pathways in the brain. “Continued drug treatment may induce processes that are the opposite of what the medication originally produced.” This may “cause a worsening of the illness [and may] continue for a period of time after discontinuation of the medication.” 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.” [Tardive Dysphoria: The Role of Long-term Antidepressant Use in Inducing Chronic Depression. El-Mallakh, R. Medical Hypotheses 76 (2011):769-773].

“A chronic and treatment-resistant depressive state is proposed to occur in individuals who are exposed to potent antagonists of serotonin reuptake pumps (i.e. SSRIs) for prolonged time periods. Due to the delay in the onset of this chronic depressive state, it is labeled tardive dysphoria. Tardive dysphoria manifests as a chronic dysphoric state that is initially transiently relieved by — but ultimately becomes unresponsive to — antidepressant medication. Serotonergic antidepressants may be of particular importance in the development of tardive dysphoria.”

Giovanni Fava elaborated further in 2011, “When we prolong treatment over 6-9 months, we may recruit processes that oppose the initial acute effects of antidepressant drugs (loss of clinical effects) . . . We may also propel the illness to a malignant and treatment-unresponsive course that may take the form of resistance or episode acceleration. When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse.”[3]

The same year, Dr. Andrews and colleagues published their examination of “oppositional tolerance,” cited earlier – which referred to “the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM” [Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression, by Paul W. Andrews1, Susan G. Kornstein, Lisa J. Halberstadt, Charles O. Gardner, and Michael C. Neale, Frontiers of Evolutionary Psychology, July 2011, Vol., Art 159].

 

Notes:

[1] Hyman, S. “Initiation and adaptation: A paradigm for understanding psychotropic drug action.” Am J Psychiatry 153 (1996):151-61.

[2] El-Mallakh, R. “Tardive dysphoria: The role of long-term antidepressant use in inducing chronic depression. Medical Hypotheses 76 (2011): 769-773.

[3] Giovanni Fava, “The mechanisms of tolerance in antidepressant action.” Progress in NeuroPsychopharmacology & Biological Psychiatry 35 (2011): 1593-1602.

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