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



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.



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.



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.
Depression Research Unit, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Jay D
JD
Amsterdam
Depression Research Unit, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Psychology, University of Pennsylvania, Philadelphia, PA, USA.|Methods to Improve Diagnostic Assessment and Services (MIDAS) Project, Brown University, Providence, RI, USA.
Lorenzo
L
Lorenzo-Luaces
Depression Research Unit, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Psychology, University of Pennsylvania, Philadelphia, PA, USA.
Robert J
RJ
DeRubeis
D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000145:classification / Q000493:pharmacokinetics; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy; D004311:Double-Blind Method; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000379:methods; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D016651:Lithium Carbonate / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D012074:Remission Induction / Q000379:methods; D055502:Secondary Prevention / Q000379:methods; D016896:Treatment Outcome; D000069470:Venlafaxine Hydrochloride / Q000008:administration & dosage / Q000493:pharmacokinetics
D000928:Antidepressive Agents; D016651:Lithium Carbonate; D000069470:Venlafaxine Hydrochloride

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