Step-wise loss of antidepressant effectiveness with repeated antidepressant trials in bipolar II depression

Bipolar Disord. 2016 Nov;18(7):563-570. doi: 10.1111/bdi.12442. Epub 2016 Nov 2.


Objective: This study examined the relationship between the number of prior antidepressant treatment trials and step-wise increase in pharmacodynamic tolerance (or progressive loss of effectiveness) in subjects with bipolar II depression.

Methods: Subjects ≥18 years old with bipolar II depression (n=129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months.

Results: After controlling for baseline covariates of prior medications, there was a 25% reduction in the likelihood of response to treatment with each increase in the number of prior antidepressant trials (odds ratio [OR]=0.75, unstandardized coefficient [B]=-0.29, standard error (SE)=0.12; χ2 =5.70, P<.02], as well as a 32% reduction in the likelihood of remission with each prior antidepressant trial (OR=0.68, B=-0.39, SE=0.13; χ2 =9.71, P=.002). This step-wise increase in pharmacodynamic tolerance occurred in both treatment conditions. Prior selective serotonin reuptake inhibitor (SSRI) therapy was specifically associated with a step-wise increase in tolerance, whereas other prior antidepressants or mood stabilizers were not associated with pharmacodynamic tolerance. Neither the number of prior antidepressants, nor the number of prior SSRIs, or mood stabilizers, were associated with an increase in relapse during continuation therapy.

Conclusions: The odds of responding or remitting during venlafaxine or lithium monotherapy were reduced by 25% and 32%, respectively, with each increase in the number of prior antidepressant treatment trials. There was no relationship between prior antidepressant exposure and depressive relapse during continuation therapy of bipolar II disorder.

Trial registration: NCT00602537.

Keywords: SNRI; SSRI; antidepressant; bipolar disorder; depression; drug tolerance; lithium; loss of response; tachyphylaxis; treatment-resistant depression; venlafaxine.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / classification
  • Antidepressive Agents / pharmacokinetics
  • Bipolar Disorder* / diagnosis
  • Bipolar Disorder* / drug therapy
  • Double-Blind Method
  • Drug Monitoring
  • Drug Therapy, Combination / methods
  • Drug Tolerance
  • Female
  • Humans
  • Lithium Carbonate* / administration & dosage
  • Lithium Carbonate* / pharmacokinetics
  • Male
  • Remission Induction / methods
  • Secondary Prevention / methods
  • Treatment Outcome
  • Venlafaxine Hydrochloride* / administration & dosage
  • Venlafaxine Hydrochloride* / pharmacokinetics


  • Antidepressive Agents
  • Lithium Carbonate
  • Venlafaxine Hydrochloride

Associated data