Could ‘Treatment Resistance’ be an Effect of Antidepressants?

Previously taking antidepressants could make individuals less likely to response to treatment for bipolar II depression


A recent article, published in Bipolar Disorders, investigates the effect of previously taking antidepressants on response to current antidepressant treatment for bipolar II disorder. The results of the analysis indicate that previous trials of antidepressant medication decrease the likelihood of responding to current treatment of venlafaxine or lithium.

“Some antidepressant drugs may produce a persistent physiological adaptation over time that manifests as progressive tolerance, and this eventual loss of effectiveness may result from repeated antidepressant administration per se,” conclude the researchers, led by Jay Amsterdam, a professor from the Department of Psychiatry at the University of Pennsylvania School of Medicine.

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Studies have found that individuals may develop pharmacodynamic tolerance to antidepressants, meaning that over time the antidepressant becomes less effective. Previous studies conducted by the authors suggest that 2050% of patients develop a tolerance to antidepressants after repeated antidepressant trials (i.e., trying multiple antidepressants). It is unclear whether the effect is due to genetic factors that predispose an individual to tolerance, or if tolerance is the result of the drug causing physical changes to neurotransmitter systems.

The authors note that the second explanation is highly concerning “because it would suggest that some cases of resistant depression results from repeated exposure to antidepressant therapy per se.”

If the second explanation is accurate, then antidepressant medication could actually have the effect of causing ‘treatment-resistant depression.’ Unintended consequences of treatment, like this, are referred to as iatrogenic effects, and many have raised concerns about the iatrogenic effects of psychiatric medication.

In an attempt to better understand what leads to treatment resistant depression, the authors analyzed data from 129 subjects who previously completed a 12-week randomized controlled trial (RCT) comparing venlafaxine to lithium for treating bipolar II depression. The researchers examined whether the number of previous antidepressant trials was related to the likelihood of responding to the medication and the risk of relapse while on the drug.

Subjects had taken, on average, 2.7 antidepressant medications before starting the RCT. Only 17% of subjects had never taken an antidepressant previously. The researchers controlled for a number of factors associated with prior antidepressant treatment (e.g., being Caucasian, not experiencing inter-episode recovery, higher baseline severity, previous depressive episodes).

Even controlling for these factors, they found “a significant association between the number of prior antidepressant trials and the likelihood of response (odds ratio [OR]=0.75, B=−0.29, SE=0.12; χ2=5.70, P<.02) and remission (OR=0.68, B=−0.39, SE=0.13; χ2=9.71, P=.002).” That is, the more antidepressants the subjects had tried previously, the less likely they were to experience treatment response or remission.

The authors summarize, “The odds of responding or remitting during acute venlafaxine or lithium monotherapy in the current study were reduced by approximately 25% and 32%, respectively, with each increase in the number of prior antidepressant trials at any time over the course of the affective illness.”

The association was most significant when the previous antidepressants were selective serotonin reuptake inhibitors (SSRIs). The researchers did not find an association between previous antidepressant trials and relapse. The authors acknowledge that the study was conducted retrospectively, which limits the strength of the conclusions that can be made.

Still, they conclude, “This may suggest that the presence of step-wise loss of effectiveness observed in the current study is not a genetic predisposition to nonresponse; rather, it suggests that it is repeated exposure to prior antidepressants that influenced the effectiveness of the venlafaxine and lithium response.”

The results of the present analysis confirm previous studies that found a “step-wise loss of antidepressant responsiveness after repeated antidepressant exposures” and extends on those studies by demonstrating that the phenomenon occurs not only for unipolar depression but also bipolar depression.

Noting that the results were most significant when previous medications were SSRIs, the authors state, “Although there has been a proliferation of SSRIs and other antidepressant drugs over the past four decades, the likelihood of achieving response and remission with these drugs has not changed, and the number of patients with persistent depression may have increased.”

The authors also highlight their previous study showing that tolerance does not result from psychotherapy as it does in pharmacotherapy.

They conclude, “This suggests that exposure to prior antidepressants may be a predictor of a poor response to subsequent drug trials and that other treatment approaches should be considered.”



Amsterdam, J. D., Lorenzo‐Luaces, L., & DeRubeis, R. J. (2016). Step‐wise loss of antidepressant effectiveness with repeated antidepressant trials in bipolar II depression. Bipolar Disorders, 18, 563-570. doi:10.1111/bdi.12442 (Abstract)


  1. May I add that the current DSM “bipolar” drug treatment recommendations, that call for combining the antidepressants and/or antipsychotics, can create what appears to the doctors to be the negative symptoms of “schizophrenia,” via neuroleptic induced deficit syndrome, and what appears to the doctors to be the positive symptoms of “schizophrenia,” via anticholinergic toxidrome. And since these iatrogenic, psychiatric drug induced illnesses are not listed in the DSM they are almost always misdiagnosed as one of the billable DSM disorders.

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  2. You talked about how amount of medication trials and going from different medications may decrease drug effectiveness.

    Here’s one for you:

    Does length of time on one medication limit possible long term adverse effects?

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