Sleep Initiation and Maintenance Disorders: Fava M

Fava M. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · J Psychopharmacol. · Pubmed #16644769 No free full text.

Abstract: Despite the efficacy of currently available antidepressant treatment, residual symptoms are common among individuals treated for major depressive disorder and are associated with an increased risk of relapse and poor psychosocial functioning. However, distinguishing treatment-emergent side effects from residual symptoms can be challenging for clinicians. Anxiety, sleep disturbance, somnolence/fatigue, apathy and cognitive dysfunction are among the more frequent residual symptoms. Approaches to the management of residual symptoms include addressing treatment-emergent side effects and co-morbid conditions, optimizing antidepressant dosing and using augmentation therapy. Clinicians are often guided in their decisions by anecdotal impressions. Studies assessing the evaluation and treatment of residual symptoms and side effects will contribute importantly to the optimal acute and long-term management of depression.

Fava M. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · J Clin Psychiatry. · Pubmed #15575802 No free full text.

Abstract: Insomnia and daytime sleepiness are often associated with depression. The possible relationships between sleep difficulties and depression are numerous. Insomnia and other sleep disturbances can be precursors to the onset of major depressive disorder, so they may act as risk factors for or predictors of depression. The symptomatology of depression also prominently includes insomnia, and sleep disturbances may be residual symptoms after response to antidepressant treatment. Insomnia and the resultant daytime sleepiness may be short-term or long-term side effects of antidepressant treatment as well. Whether insomnia is a precursor, symptom, residual symptom, or side effect of depression or its treatment, clinicians must give serious attention to and attempt to resolve sleep disturbances because of the risk of depression onset, worsening of depressive symptoms, and relapse of depression after response to antidepressant treatment. Remission of depression cannot be fully achieved until the associated insomnia and daytime sleepiness are resolved. This article describes the relationships between insomnia and depression and discusses the effects of various antidepressants on sleep. Finally, several different treatment options, including antidepressant monotherapy and augmentation of antidepressants with other medications, are explored.

Fava M, Hoog SL, Judge RA, Kopp JB, Nilsson ME, Gonzales JS. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · J Clin Psychopharmacol. · Pubmed #11910258 No free full text.

Abstract: This study assessed whether fluoxetine, sertraline, and paroxetine differ in efficacy and tolerability in depressed patients and the impact of baseline insomnia on outcomes. Patients (N = 284) with DSM-IV major depressive disorder were randomly assigned in a double-blind fashion to fluoxetine, paroxetine, or sertraline for 10 to 16 weeks of treatment. Using the Hamilton Rating Scale for Depression (HAM-D) sleep disturbance factor score, patients were categorized into low (<4) or high (>or=4) baseline insomnia subgroups. Changes in depression and insomnia were assessed. Safety assessments included treatment-emergent adverse events (AEs), reasons for discontinuation, and AEs leading to discontinuation. In addition, AEs were evaluated within insomnia subgroups to determine emergence of activation or sedation. Depression improvement, assessed with the HAM-D-17 total score, was similar among treatments in all patients (p = 0.365) and the high (p = 0.853) and low insomnia (p = 0.415) subgroups. Insomnia improvement, assessed with the HAM-D sleep disturbance factor score, was similar among treatments in all patients (p = 0.868) and in the high (p = 0.852) and low insomnia (p = 0.982) subgroups. Analyses revealed no significant differences between treatments in the percentages of patients with substantial worsening, any worsening, worsening at endpoint, or improvement at endpoint in the HAM-D sleep disturbance factor in either insomnia subgroup. Treatments were well tolerated in most patients. No significant differences between treatments in the incidence of AEs suggestive of activation or sedation were seen in the insomnia subgroups. These data show no significant differences in acute treatment efficacy and tolerability across fluoxetine, sertraline, and paroxetine in major depressive disorder patients. Improvement in overall depression and in associated insomnia was achieved by most patients regardless of baseline insomnia.

Krystal A, Fava M, Rubens R, Wessel T, Caron J, Wilson P, Roth T, McCall WV. · Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. · J Clin Sleep Med. · Pubmed #17557453 No free full text.

Abstract: BACKGROUND: Insomnia and major depressive disorder (MDD) may coexist. This study evaluated hypnotic discontinuation effects following an 8-week placebo-controlled study of eszopiclone/fluoxetine cotherapy in patients with insomnia and comorbid MDD. METHODS: Patients meeting DSM-IV criteria for MDD and insomnia received fluoxetine each morning for 8 weeks and were randomized to concomitant treatment with nightly eszopiclone 3 mg (cotherapy) or placebo (monotherapy). Thereafter, patients received 2 weeks of continued fluoxetine plus single-blind placebo. RESULTS: Incidence rates of central nervous system (CNS) and potentially CNS-related adverse events (AEs) during the run-out period were similar between treatment groups (8.8% with monotherapy vs 9.8% with cotherapy), and there was no evidence of benzodiazepine withdrawal AEs. Physician-assessed Clinical Global Impression improvements in depressive symptoms were maintained after eszopiclone discontinuation. Improvements in 17-item Hamilton-Depression Rating Scale (HAMD-17) scores with cotherapy versus monotherapy seen at Week 8 (p = .0004) were maintained at Week 10 (p < .0001) and significantly higher depression response and remission rates were observed after cotherapy at Week 10 (p < .02). Patients discontinued from eszopiclone maintained improvements in SL (sleep latency), WASO (wake after sleep onset), and TST (total sleep time) during the 2 weeks following discontinuation (p < .05). CONCLUSIONS: In this study, eszopiclone discontinuation did not result in significant CNS or benzodiazepine withdrawal AEs, rebound insomnia, or rebound depression; and improvements in sleep and depressive symptoms were maintained.

Papakostas GI, Fava M. · Department of Psychiatry, Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Can J Psychiatry. · Pubmed #17168253 No free full text.

Abstract: OBJECTIVE: To compare response rates among patients with major depressive disorder (MDD) treated with either moclobemide, an antidepressant thought to simultaneously enhance both noradrenergic and serotonergic neurotransmission, or selective serotonin reuptake inhibitors (SSRIs). METHODS: Using a random-effects model, we combined 12 trials involving 1207 outpatients with MDD. RESULTS: Patients treated with moclobemide were as likely to experience clinical response as those treated with SSRIs (risk ratio 1.08; 95% confidence interval, 0.92 to 1.26; P = 0.314). Simply pooling response rates for the 2 agents resulted in a 62.1% response rate for moclobemide and a 57.5% response rate for the SSRIs. A metaregression did not reveal a statistically significant relation between the mean moclobemide dosage for each study and the risk ratio for response rates. Further, we found no difference between the 2 treatments in overall discontinuation rates, discontinuation rates due to adverse events, or discontinuation rates due to lack of efficacy. Also, rates of fatigue or somnolence and of insomnia were similar between the 2 treatment groups. However, SSRI treatment was associated with higher rates of nausea, headaches, and treatment-emergent anxiety than was treatment with moclobemide. CONCLUSIONS: These results suggest that moclobemide and the SSRIs do differ with respect to their side effect profiles but not in their overall efficacy in the treatment of MDD.

Fava M, McCall WV, Krystal A, Wessel T, Rubens R, Caron J, Amato D, Roth T. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · Biol Psychiatry. · Pubmed #16581036 No free full text.

Abstract: BACKGROUND: Insomnia and major depressive disorder (MDD) can coexist. This study evaluated the effect of adding eszopiclone to fluoxetine. METHODS: Patients who met DSM-IV criteria for both MDD and insomnia (n = 545) received morning fluoxetine and were randomized to nightly eszopiclone 3 mg (ESZ+FLX) or placebo (PBO+FLX) for 8 weeks. Subjective sleep and daytime function were assessed weekly. Depression was assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Impression Improvement (CGI-I) and Severity items (CGI-S). RESULTS: Patients in the ESZ+FLX group had significantly decreased sleep latency, wake time after sleep onset (WASO), increased total sleep time (TST), sleep quality, and depth of sleep at all double-blind time points (all p < .05). Eszopiclone co-therapy also resulted in: significantly greater changes in HAM-D-17 scores at Week 4 (p = .01) with progressive improvement at Week 8 (p = .002); significantly improved CGI-I and CGI-S scores at all time points beyond Week 1 (p < .05); and significantly more responders (59% vs. 48%; p = .009) and remitters (42% vs. 33%; p = .03) at Week 8. Treatment was well tolerated, with similar adverse event and dropout rates. CONCLUSIONS: In this study, eszopiclone/fluoxetine co-therapy was relatively well tolerated and associated with rapid, substantial, and sustained sleep improvement, a faster onset of antidepressant response on the basis of CGI, and a greater magnitude of the antidepressant effect.

Perlis RH, Mischoulon D, Smoller JW, Wan YJ, Lamon-Fava S, Lin KM, Rosenbaum JF, Fava M. · Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA. · Biol Psychiatry. · Pubmed #14573314 No free full text.

Abstract: BACKGROUND: The short (S) allele of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been associated with poorer antidepressant response in major depressive disorder (MDD) and with antidepressant-induced mania. This study investigated a possible association with treatment-emergent insomnia or agitation. METHODS: Thirty-six outpatients with MDD were genotyped at 5HTTLPR and treated with open-label fluoxetine up to 60 mg/day. Treatment-emergent adverse effects were assessed at each study visit. RESULTS: Of nine subjects homozygous for the "S" allele, seven (78%) developed new or worsening insomnia, versus 6 of 27 (22%) non-"S"-homozygous subjects (Fisher's exact p =.005). Similarly, six of nine subjects homozygous for the "S" allele (67%) developed agitation, versus 2 of 27 (7%) of non-"S"-homozygous subjects (Fisher's exact p =.001). CONCLUSIONS: The "S" allele of the 5HTTLPR may identify patients at risk for developing insomnia or agitation with fluoxetine treatment. This preliminary result requires confirmation in larger samples.

Dording CM, Mischoulon D, Petersen TJ, Kornbluh R, Gordon J, Nierenberg AA, Rosenbaum JE, Fava M. · Depression Clinical and Research Group, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Ann Clin Psychiatry. · Pubmed #12585563 No free full text.

Abstract: Despite the superior side effect profile of the newer antidepressants over the tricyclics and monoamine oxidase inhibitors, all newer antidepressants are associated with a wide array of side effects. Clinicians are constantly confronted with the challenge of managing these side effects in the context of minimal research to prove one management strategy is more effective than another. The purpose of this study was to examine prescribing practices regarding the management of SSRI-associated side effects in a sample of psychiatrists attending a psychopharmacology review course. A total of 439 out of 800 clinicians (55%) attending a psychopharmacology review course responded to our questionnaire that was given prior to beginning the review course, though not all respondents answered all four items on the questionnaire. Among these items were questions designed to assess clinician preference for the management of SSRI-induced side effects. As a treatment for SSRI-induced sexual dysfunction, 43% (143/330) chose adding bupropion, while 36% (120/330) opted to switch agents as their first choice; for SSRI-induced insomnia, 78% (264/326) chose adding trazodone. Switching agents was the first choice of 61% (214/353) of clinicians for managing SSRI-induced agitation, 93% (339/363) for managing SSRI-associated weight gain. In an effort to manage most SSRI-associated side effects (with the exception of sexual dysfunction and insomnia), the majority of the clinicians responding to our survey opted to switch agents rather than add a specific medication to the existing SSRI. In our opinion, this practice may reflect the relative lack of research studies on the role of adjunctive treatments in the management of SSRI-induced side effects and/or the tendency to favor monotherapy over polypharmacy.