Short-term cotherapy with clonazepam and fluoxetine: anxiety, sleep disturbance and core symptoms of depression

J Affect Disord. 2000 Dec;61(1-2):73-9. doi: 10.1016/s0165-0327(99)00195-0.


Background: SSRIs resolve depression slowly and may increase anxiety or insomnia. Adding clonazepam to fluoxetine sped response, raising the question of mechanism of action: reducing symptoms co-existing with depression, suppressing side-effects, and/or alleviating core depressive symptoms.

Method: Adult outpatients randomly assigned to double-blind treatment with fluoxetine 20 mg+placebo or fluoxetine+clonazepam 0.5-1.0 mg were assessed by a HAM-D anxiety cluster, sleep disturbance cluster, and core symptoms cluster.

Results: No serious AEs were noted; no cotherapy patients dropped for AEs. Cotherapy proved superior (HAM-D total, anxiety cluster, sleep disturbance cluster ANOVA P<0.001; core symptoms P<0.011). Treatment-emergent anxiety was reported for 25% of placebo patients and 7% of cotherapy patients (P<0.037); sleep disturbance for 10% of placebo patients and no cotherapy patients (P<0.055). Sedation and dry mouth were more common for cotherapy treatment (P>0.20).

Limitations: Extended treatment and refractory depression were not addressed.

Conclusions: Low-dose cotherapy of fluoxetine with clonazepam was safe and accelerated response over 21 days of treatment, decreasing anxiety and sleep disturbance as symptoms and partially suppressed them as SSRI side-effects; it also modestly reduced core symptoms of low mood and loss of interest.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anxiety / diagnosis
  • Anxiety / drug therapy*
  • Clonazepam / administration & dosage
  • Clonazepam / therapeutic use*
  • Depressive Disorder, Major / diagnosis
  • Depressive Disorder, Major / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Female
  • Fluoxetine / administration & dosage
  • Fluoxetine / adverse effects
  • Fluoxetine / therapeutic use*
  • GABA Modulators / administration & dosage
  • GABA Modulators / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*
  • Sleep Wake Disorders / diagnosis
  • Sleep Wake Disorders / drug therapy*
  • Time Factors
  • Treatment Outcome


  • GABA Modulators
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Clonazepam