Residual sleep disturbance and risk of relapse during the continuation/maintenance phase treatment of major depressive disorder with the selective serotonin reuptake inhibitor fluoxetine

Background  

Relapse of major depressive disorder (MDD) is a common clinical problem. This study was designed to determine whether residual sleep disturbance (insomnia and hypersomnia) predict risk of relapse during the continuation and maintenance treatment of MDD.     

Predictors of relapse during fluoxetine continuation or maintenance treatment of major depression

BACKGROUND: The goal was to examine predictors of relapse during continuation/maintenance treatment of major depression that had remitted following 12 to 14 weeks of fluoxetine therapy. METHOD: The study utilizes data collected in a collaborative clinical trial including patients with DSM-III-R major depression at 5 university-affiliated outpatient psychiatry clinics. Three hundred ninety-five patients who remitted with fluoxetine therapy were randomly assigned to 1 of 4 treatments: fluoxetine for 14 weeks followed by placebo for 36 weeks, fluoxetine for 38 weeks followed by placebo for 12 weeks, fluoxetine for 50 weeks, or placebo for 50 weeks. Cox proportional hazard models were used to identify predictors of time to relapse. RESULTS: In addition to the previously reported longitudinal pattern of response during acute treatment, neurovegetative symptom pattern was a predictor of fluoxetine benefit compared with placebo. Greater chronicity predicted poorer survival, which was not differential by treatment. The most robust advantage of fluoxetine was seen for patients with endogenous vegetative symptoms, chronic depression, and acute treatment response characterized by onset in the third week or later and persistence of response once attained. CONCLUSION: Both nonspecific pattern of response and neurovegetative symptoms characteristic of atypical depression were predictive of lack of fluoxetine efficacy in continuation/ maintenance treatment. These findings have importance for both clinical management and analyses of future maintenance trials.     

文拉法辛对选择性5-羟色胺再摄取抑制剂治疗无效的抑郁症患者的疗效

目的研究文拉法辛对选择性5羟色胺再摄取抑制剂(SSRI)治疗无效的抑郁症患者的治疗效果。方法对经SSRI治疗8周而无明显疗效的34例抑郁症患者以文拉法辛治疗6周(研究组),剂量为(100±20)mg/d。在文拉法辛治疗前及治疗后第1,2,4,6周末评定汉密尔顿抑郁量表(17项,HAMD),并进行临床疗效评定,监测血压,记录不良反应。选择同期门诊34例年龄、诊断与研究组相匹配的患者作为对照组,给予文拉法辛治疗6周,剂量为(99±25)mg/d。结果两组患者的HAMD评分均从第1周末起明显下降(P<005或P<001),且一直持续至治疗第6周末。研究组治疗第6周末的有效率达68%(23/34),临床治愈率达53%(18/34);对照组分别为77%(26/34)和59%(20/34)。两组间的差异无统计学意义(P>005)。研究组口干、恶心、呕吐的发生率高于对照组,差异有统计学意义(P<005)。结论文拉法辛对SSRI治疗8周而无明显疗效的抑郁症患者有较好的疗效。     

Sexsomnia during treatment with a selective serotonin reuptake inhibitor

Sexsomnia is a parasomnia characterised by sexual behaviour. A 30-year-old man, with no history of parasomnias or related precipitating factors, developed sexual behaviour during sleep after three weeks of treatment with escitalopram 10 mg daily. The parasomnia disappeared on the sixth day after the escitalopram had been stopped. The temporal relationship between the use of this selective serotonin reuptake inhibitor and the occurrence of the parasomnia suggests a causal relationship, possibly related to increased serotonergic neurotransmission in the raphe nucleus.     

Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder

BACKGROUND: Due to their favorable side effect profile, atypical antipsychotic agents offer important therapeutic advantages in mood disorders. Aripiprazole, an atypical antipsychotic agent with partial dopaminergic and serotonin 1A receptor agonist activity, may be particularly useful when used in conjunction with standard antidepressants in treatment-resistant depression. The purpose of this study was to test this hypothesis in depressed outpatients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor (SSRI). METHOD: 12 patients (mean +/- SD age = 46.6 +/- 11.3 years, 66.7% female) with major depressive disorder (MDD) diagnosed by use of the Structured Clinical Interview for DSM-IV-Axis I Disorders, who had failed to experience a clinical response following an adequate trial of an SSRI, were treated with open-label aripiprazole in addition to their SSRI for 8 weeks. Clinical response was defined as a 50% or greater decrease in depressive symptoms during the course of the trial (baseline-endpoint) as measured by the 17-item Hamilton Rating Scale for Depression total score. Data were collected from August 2003 to July 2004. RESULTS: 9/12 (75.0%) patients completed the trial. Using a completer analysis, 5/9 (55.6%) patients were classified as responders. An intent-to-treat (ITT) analysis resulted in 7 responders (58.3%). The overall proportion of remitters was 3/9 (33.3%) using a completer analysis and 5/12 (41.7%) using the ITT analysis. Aripiprazole administration appeared safe, with no severe adverse events observed in any of the study participants. CONCLUSIONS: These results suggest a possible augmentation role for aripiprazole when used in conjunction with SSRIs in SSRI-resistant MDD.     

Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse

Background: Many patients with major depressive disorder (MDD) who achieve full remission after antidepressant treatment still have residual depressive symptoms. In this study, we assess the type and frequency of residual symptoms and their relationship to subsequent depressive relapses after remission of major depression with fluoxetine. Method: Five hundred seventy‐six patients with MDD were openly treated with fluoxetine for 12 weeks. Those who responded underwent random assignment, under double‐blind conditions, to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse. The presence of residual symptoms in patients who achieved remission at the end of the acute phase (N=203) was assessed using the 28‐item Hamilton Depression Rating Scale. Survival analysis was used to examine the effect of residual symptoms on relapse in remitters. Results: More than 90% of patients who met criteria for remission had at least one residual depressive symptom (median=4). The most common were sleep disturbances (insomnia 48.2%, hypersomnia 35.9%) and anxiety (52.7%). The most common individual symptom was middle insomnia (33.5%). No statistically or clinically significant differences in baseline variables were found between remitters with and without residual symptoms. The presence of residual symptoms, the presence of residual insomnia and the global number of residual symptoms did not predict relapse during the continuation phase of the study. Conclusion: The great majority of patients with remission of MDD after treatment with fluoxetine continue to experience selected residual depressive symptoms. The presence of residual symptoms is not significantly associated with an increased risk of relapse. Depression and Anxiety, 2011. © 2010 Wiley‐Liss, Inc.     

Newborn neurobehavioral patterns are differentially related to prenatal maternal major depressive disorder and serotonin reuptake inhibitor treatment

Background: Prenatal serotonin reuptake inhibitor (SRI) exposure has been related to adverse newborn neurobehavioral outcomes; however, these effects have not been compared to those that may arise from prenatal exposure to maternal major depressive disorder (MDD) without SRI treatment. This study examined potential effects of MDD with and without SRI treatment on newborn neurobehavior. Methods: This was a prospective, naturalistic study. Women were seen at an outpatient research center twice during pregnancy (26–28 and 36–38 weeks gestational age (GA)). Psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM‐IV; medication use was measured with the Timeline Follow‐Back instrument. Three groups were established based upon MDD diagnosis and SRI use: Control (N = 56), MDD (N = 20), or MDD + SRI (N = 36). Infants were assessed on a single occasion within 3 weeks of birth with the NICU Network Neurobehavioral Assessment Scale. Generalized Linear Modeling was used to examine neurobehavioral outcomes by exposure group and infant age at assessment. Results: Full‐term infants exposed to MDD + SRIs had a lower GA than CON or MDD‐exposed infants and, controlling for GA, had lower quality of movement and more central nervous system stress signs. In contrast, MDD‐exposed infants had the highest quality of movement scores while having lower attention scores than CON and MDD + SRI‐exposed infants. Conclusion: MDD + SRI‐exposed infants seem to have a different neurobehavioral profile than MDD‐exposed infants in the first 3 weeks after delivery; both groups may have different neurobehavioral profiles with increasing age from birth. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc.     

Relationship of variability in residual symptoms with recurrence of major depressive disorder during maintenance treatment

OBJECTIVE: To investigate how residual symptoms from an index episode of major depressive disorder may be associated with recurrence, the authors conducted a trial involving four maintenance treatment approaches and examined 1) whether the level and variability of residual symptoms differed among the maintenance treatment conditions and 2) whether greater symptom variability is associated with a higher likelihood of recurrence and more rapid recurrence. METHOD: Patients enrolled in a maintenance treatment study (N=114) were randomly assigned to one of four maintenance treatment conditions: imipramine plus interpersonal psychotherapy, imipramine alone, interpersonal psychotherapy alone, or no active treatment. Residual symptoms were characterized both as continuous variables (mean values and coefficients of variation for Hamilton Depression Rating Scale and Global Assessment Scale [GAS] scores) and as a categorical variable, the percentage of maintenance evaluations with a Hamilton depression scale score > or =8 (e.g., with a symptom peak). RESULTS: Analysis of variance revealed no differences among the four treatment conditions in patients' levels of residual symptoms or symptom variability assessed as a continuous variable, but patients in the combined treatment group had fewer symptom peaks, compared to those in the placebo and interpersonal psychotherapy groups. Cox proportional hazards modeling showed that higher coefficients of variation for both the Hamilton depression scale and the GAS scores and a greater percentage of evaluations with symptom peaks were associated with shorter survival times. CONCLUSIONS: A higher level of symptom variability during maintenance treatment is associated with higher risk for recurrence of depression and may provide a specific target for maintenance treatments.     

A metaanalysis of clinical trials comparing moclobemide with selective serotonin reuptake inhibitors for the treatment of major depressive disorder.

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.     

Patient compliance to a new enteric-coated weekly formulation of fluoxetine during continuation treatment of major depressive disorder

BACKGROUND: A new formulation of enteric-coated fluoxetine given once weekly could be a useful option for the long-term treatment of depression, but compliance to once-weekly fluoxetine treatment has not been assessed. METHOD: Patients were adults from the United Kingdom who had responded to fluoxetine treatment for a current episode of depression (DSM-IV criteria). In the baseline assessment phase, all patients (N = 117) were continued on 20 mg of open-label fluoxetine once daily for 4 weeks. In the follow-up phase, patients (N = 109) were randomly assigned to once-weekly or once-daily fluoxetine for 3 months. Patient compliance was monitored by electronic devices during both phases of the study. RESULTS: Compliance to once-weekly fluoxetine treatment was higher than compliance to once-daily fluoxetine (85.9% vs. 79.4%, respectively). CONCLUSION: Once-weekly fluoxetine treatment allows for new flexibility for both the clinician and the patient, and this study alleviates the concern that patients will forget weekly doses.     

On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor

Antidepressant drugs are reported to be used as co-analgesics in clinical management of migraine and neuropathic pain. The mechanism through which they alleviate pain remains unknown. The present study explores the possible mechanism of a selective serotonin reuptake inhibitor (SSRI) fluoxetine-induced antinociception in animals. Acetic acid-induced writhing, hot plate and tail-flick test were used to assess fluoxetine-induced antinociception. Fluoxetine (5-20 mg kg(-1), i.p.) produced a significant and dose-dependent antinociceptive effect against acetic acid-induced writhing in mice. Fluoxetine (20 mg kg(-1)) also exhibited antinociceptive effect in tail flick as well as hot plate assays. Further, i.c.v. administration of fluoxetine showed significant antinociception against writhing test in rats. However, fluoxetine (1 microg/10 microl/rat, i.c.v.) did not exhibit any antinociceptive effect in serotonin-depleted animals. Further, pindolol (10 mg kg(-1), i.p.) enhanced fluoxetine-induced antinociceptive effect. The antinociceptive effect of fluoxetine was sensitive to blockade by naloxone (5 mg kg(-1), i.p.) and naltrexone (5 mg kg(-1), i.p.). These data suggest that fluoxetine-induced antinociception involves both central opioid and the serotoninergic pathways.     

Effect of fluoxetine treatment on serotonin and MHPG in 32 patients with major depressive disorder

Considering the concept that depressive disorders were not only resulting from activity of one neurotransmitter, possible interactions between the noradrenergic system and a selective serotonin uptake inhibitor, fluoxetine, were investigated in order to test the hypothesis of noradrenergic or serotonergic involvement in depression. So the biological parameters (plasma and urinary MHPG, platelet serotonin) were evaluated by HPLC. The aim of this study was to evaluate the correlations between the concentrations of MHPG and serotonin in 32 melancholic patients treated by fluoxetine (20 mg/day) during a minimum of three weeks. The clinical examination with evaluation of the antidepressant effect carried out using the HDS/MES rating scale, allowed to divide the patients into three groups: responders to treatment, partial responders and non responders. In the same time, a control group of healthy subjects was investigated. ANOVA applied to platelet serotonin at day 0 showed a tendency toward heterogeneity between the three patient groups and the control group. The concentrations of serotonin in the three patients groups were highly reduced after 21 days of treatment. Concerning plasma and urinary MHPG there was non significant difference among the three patients groups at day 0 and the control groups. After treatment by fluoxetine, the results suggest that the urinary sulfate MHPG is an indicator of the metabolism of brain norepinephrine and seems to be a better turnover indicator than the plasma sulfate MHPG. The selective evaluation of sulfate and glucuronide MHPG could give a better survey of the psychobiological state of the patients than the total MHPG evaluation.     

Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder

BACKGROUND: Due to their favorable side-effect profile, atypical antipsychotic agents offer important therapeutic advantages in mood disorders. Ziprasidone, an atypical antipsychotic agent with strong 5-HT(1A) agonist activity, may be particularly useful when used in conjunction with standard antidepressants in treatment-resistant depression. The purpose of this study is to test this hypothesis in depressed outpatients who have not experienced significant clinical improvement following an adequate trial of a selective serotonin reuptake inhibitor (SSRI). METHOD: Twenty patients with major depressive disorder (MDD) who had failed to experience a clinical response to an adequate trial of an SSRI were treated with open-label ziprasidone in addition to their SSRI for 6 weeks between February 2002 and December 2002. MDD was diagnosed with the Structured Clinical Interview for DSM-IV Axis I disorders. Clinical response was defined as a 50% or greater decrease in depressive symptoms during the course of the trial (baseline to endpoint), as measured by the HAM-D-17 total score. RESULTS: Thirteen of 20 patients (65.0%) completed the trial. Using a completer analysis, 8 patients (61.5%) were classified as responders. An intent-to-treat (ITT) analysis resulted in 10 responders (50.0%). The overall proportion of remitters was 5 of 13 (38.5%) using a completer analysis and 5 of 20 (25.0%) using the ITT analysis. Ziprasidone administration appeared to be safe, with no clinically significant QTc prolongation or severe adverse events observed in any of the study participants. CONCLUSION: These results suggest a possible augmentation role for ziprasidone when used in conjunction with SSRIs in SSRI-resistant MDD.     

选择性5-羟色胺再摄取抑制剂治疗无效抑郁症患者换用文拉法辛与锂强化治疗的对照研究

目的:比较文拉法辛与碳酸锂强化治疗对选择性5-羟色胺再摄取抑制剂(SSRI)治疗无效的抑郁症患者的疗效和安全性. 方法:将SSRI治疗无效的抑郁症患者随机分为两组,分别予文拉法辛替换SSRI治疗和加用碳酸锂强化治疗.在治疗前及治疗1、2、4、8周采用汉密尔顿抑郁量表(HAMD)评分评定临床疗效.采用治疗中出现的症状量表(TESS)评定药物安全性. 结果:文拉法辛组治疗痊愈率为51.1％,锂强化组治疗痊愈率为28.9％,两组痊愈率差异有统计学意义(P＜0.05).结论:SSRI治疗无效的抑郁症患者换用文拉法辛的疗效优于碳酸锂强化治疗.     

Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset of therapeutic effects in patients with major depressive disorder and fatigue

BACKGROUND: Benefit from selective serotonin reuptake inhibitor (SSRI) treatment in major depressive disorder (MDD) usually takes several weeks. Typically, a third of patients achieve remission and roughly half achieve response with acute treatment. This open-label study evaluated the efficacy and safety of modafinil treatment initiated with an SSRI in patients with MDD and fatigue. METHOD: Twenty-nine patients with DSM-IV MDD, free from antidepressant therapy (> or = 4 weeks), were administered modafinil (titrated to 200 mg/day) and fluoxetine or paroxetine (20 mg/day) for 6 weeks. Assessments included the 21-item Hamilton Rating Scale for Depression (HAM-D), Structured Interview Guide for the HAM-D (SIGH-D), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS). The SIGH-D ratings were videotaped and rated by an independent rater masked to the visit schedule. Data were collected from August 2002 through March 2003. RESULTS: Modafinil combined with an SSRI at treatment initiation significantly improved mean total SIGH-D scores within 1 week (-9.3, p <.001), and this improvement was progressive throughout the study (-21.2 at week 6, p <.001). Forty-two percent (11 of 26) and 79% (19 of 24) of patients were responders, and 39% (10 of 26) and 58% (14 of 24) of patients were remitters (HAM-D) by week 2 and week 6, respectively. Adjunct modafinil rapidly and significantly reduced fatigue (FSS score reduction from baseline = 0.7 at week 1, p <.01) and improved wakefulness (ESS score reduction from baseline = 3.6 at week 1, p <.01). The combination caused few adverse events, with nausea and headache being the most common. CONCLUSION: Modafinil combined with an SSRI at treatment initiation may enhance the onset and degree of symptom benefit in patients with MDD and fatigue. Treatment with adjunct modafinil was generally well tolerated, with most adverse effects being mild or moderate in severity.     

Imaging the serotonin transporter during major depressive disorder and antidepressant treatment

This paper focuses on serotonin transporter 5-HTT imaging to investigate major depressive disorder (MDD) and antidepressant occupancy. Such investigations have only recently been possible as a result of major advances in ligand development. The state of the art method is [11C]DASB PET or [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) positron emission tomography. [11C]DASB is a breakthrough for brain imaging 5-HTT. Compared with previous radioligands, [11C]DASB offers both high selectivity and a favourable ratio of specific binding relative to free and nonspecific binding. These characteristics contribute to valid, reliable quantitation of the 5-HTT binding potential (BP). The 5-HTT BP can be viewed as an index of 5-HTT density in a medication free state, or unblocked 5-HTT density in a medication-treated state. During major depressive episodes with no other axis I comorbidity, either no difference in regional 5-HTT BP or a trend toward elevated 5-HTT BP is typically found. During major depressive episodes (of MDD) with more severe symptoms of pessimism (dysfunctional attitudes), regional 5-HTT BP is elevated. In subjects with major depressive episodes and comorbid axis I psychiatric illnesses, decreased regional 5-HTT BP is often reported. With selective serotonin reuptake inhibitor (SSRI) treatment at doses that distinguish from placebo in the treatment of major depressive episodes, 5-HTT occupancy is approximately 80%, and there is a strong relation between plasma level and occupancy that is not predictable based on affinity alone. Implications of 5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed.