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Child Psychiatrist /Adult Psychiatrist

Early Sleep Improvement and Response to Pharmacotherapy in Psychotic Depression

Does early improvement in insomnia predict response to pharmacotherapy in psychotic depression? Authors performed a secondary analysis of a randomized clinical trial.

A woman is having hard time to sleep in her room.


“Mr Penn” is a 34-year-old Caucasian male with a history of recurrent, severe major depressive disorder (MDD) with psychotic features. His most recent psychiatric hospitalization was preceded by a period of significant insomnia with subsequent worsening depression, suicidal ideation with a plan, and an increase in paranoia.

During the hospitalization, Mr Penn was started on mirtazapine 15 mg at bedtime. Over the next 7 days, he noted significant improvement in insomnia, with resolution of his suicidal ideation and some improvements in depressive symptoms. At his hospital discharge visit, he asks about whether his dose of mirtazapine should be increased. As his psychiatrist, how would you respond?

Insomnia is a common symptom and part of the diagnostic criteria for MDD. A systematic review found that treatment of insomnia improves mood symptoms in MDD. There is some evidence that early insomnia improvement (EII) within the initial weeks of treatment predicts response to antidepressants.

However, the clinical utility of EII as a predictor of outcomes of antidepressant treatment remains unclear. There is evidence that psychotic depression (ie, MDD with psychotic features) has a higher severity of insomnia and depressive symptoms and a lower response to antidepressants than nonpsychotic MDD.

The Current Study

Vos and colleagues6 investigated whether EII predicts response and remission of psychotic depression. The authors performed a secondary analysis of the Dutch University Depression Group (DUDG),7 a double-blind randomized controlled trial of venlafaxine, imipramine, and venlafaxine plus quetiapine in psychotic depression. Participants were aged 18 to 65 years and had a DSM-IV-TR diagnosis of psychotic depression. They had a Hamilton Rating Scale for Depression (HAM-D-17) score of ≥18.

Exclusion criteria were no insomnia symptoms at baseline, acute indication for ECT, IA <80, alcohol or substance use disorder in the past 3 months, serious somatic illness, somatic medication affecting mood symptoms, and contraindications for or previous treatment with venlafaxine or imipramine during the current depressive episode.

Patients were randomized to 7 weeks of double-blind treatment with venlafaxine, imipramine, or venlafaxine plus quetiapine. A maximum of 3 mg lorazepam per day was also permitted. Depressive symptoms were rated weekly using the HAM-D-17. EII was defined as a ≥20% reduction of insomnia severity (sum of the 3 sleep-related HAM-D-17 items) from baseline after 2 weeks of treatment. Early response for depression was defined as ≥20% reduction in HAM-D-17 score after 2 weeks.

The primary outcome measure was response for depression, defined as ≥50% reduction in HAM-D-17 score after 7 weeks (excluding the 3 sleep-related outcomes for the association with EII). Remission of depression was defined as a HAM-D-17 score <8 and the absence of hallucinations and delusions after 7 weeks. Associations between EII and outcomes were analyzed using logistic regression models controlled for age, sex, medication, benzodiazepine use, and pre-treatment insomnia and depression scores. The authors used a last observation carried forward approach for study dropouts.

Approximately 114 participants (out of 122 in the original study) met the inclusion/exclusion criteria and were analyzed. Thirty-seven received venlafaxine, 38 imipramine, and 39 venlafaxine plus quetiapine. There were no significant differences in clinical or demographic factors based on the treatment group. The mean participant age was 51 years, and 48% of participants were male.

Over the first 2 weeks, the average reduction in insomnia symptoms was significantly greater than other depressive symptoms. EII was achieved in 74% and early response on overall depression in 67% of patients. After 7 weeks, depression response was achieved in 57% and remission in 32%, as well as remission of psychotic symptoms in 67%.

EII was a significant predictor of response on overall depression (OR=7.9, 95% CI 2.7-23.4) and depression excluding the 3 insomnia items (OR=6.3m 95% I 2.2-18.3). EII was also a significant predictor of remission of depression (OR=6.1, 95% CI 1.6-23.3) and remission of psychotic symptoms (OR=4.1, 95% CI 1.6-10.9). There were no significant interactions between EII and medications. EII had a higher sensitivity and negative predictive value than early depression response for all outcome measures.

Study Conclusions

The authors performed the first study of EII as a predictor of treatment outcome in psychotic depression. They found evidence that EII was associated with depression response and remission and remission of psychosis. Insomnia symptoms improved within the first weeks of pharmacotherapy, whereas depressive symptoms improved more gradually.

Study strengths include a more homogeneous sample of patients with psychotic depression, and the fact that patients were free of other psychotropics (except possibly low-dose benzodiazepines). Limitations include the lack of data on pre-study benzodiazepines and the lack of a specific insomnia scale.

The Bottom Line

Early improvement in insomnia was associated with a higher response to depressive and psychotic symptoms in psychotic depression. Further studies are needed to investigate the generalizability of EII as a predictor of treatment response in depression.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


Related topic:



1. Gebara MA, Siripong N, DiNapoli EA, et al. Effect of insomnia treatments on depression: a systematic review and meta-analysis. Depress Anxiety. 2018;35(8):717-731.

2. Cao B, Park C, Rosenblat JD, et al. Changes in sleep predict changes in depressive symptoms in depressed subjects receiving vortioxetine: an open-label clinical trial. J Psychopharmacol. 2019;33(11):1388-1394.

3. Wang M, Zhang B, Zhou Y, et al. Sleep improvement is associated with the antidepressant efficacy of repeated-dose ketamine and serum BDNF levels: a post-hoc analysis. Pharmacol Rep. 2021;73(2):594-603.

4. Manber R, Buysse DJ, Edinger J, et al. Efficacy of cognitive-behavioral therapy for insomnia combined with antidepressant pharmacotherapy in patients with comorbid depression and insomnia: a randomized controlled trial. J Clin Psychiatry. 2016;77(10):e1316-e1323.

5. Jääskeläinen E, Juola T, Korpela H, et al. Epidemiology of psychotic depression - systematic review and meta-analysis. Psychol Med. 2018;48(6):905-918.

6. Vos CF, Birkenhäger TK, Nolen WA, et al. The relationship of early sleep improvement with response to pharmacotherapy in unipolar psychotic depression [published online ahead of print, 2023 Aug 31]. J Clin Psychopharmacol. 2023;10.1097/JCP.0000000000001756.

7. Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand. 2010;121(3):190-200.


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