Cognitive therapy does not prevent a response to tryptophan depletion in patients also treated with antidepressants.

BACKGROUND: Acute tryptophan depletion (ATD) induces depressive symptoms in remitted depressed patients treated with serotonergic medications, but not in patients treated with noradrenergic medications or electroconvulsive therapy. A recent study suggests that cognitive therapy (CT) protects against the effects of ATD, but the evidence is questionable. The present study compared the effect of ATD in patients who were treated with antidepressant medication and CT (n = 17) versus antidepressant medication alone (n = 23) during their latest episode. METHODS: Forty remitted depressed patients underwent high-dose and low-dose ATD in a randomized double-blind crossover design. RESULTS: There were no differences in response to ATD between treatment groups. This applied to groups defined by lifetime and by recent CT experience. CONCLUSIONS: Cognitive therapy does not protect against the effects of rapidly lowered plasma tryptophan levels in remitted depressed patients who are also treated with antidepressant medication.     

Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms.

BACKGROUND: Acute tryptophan depletion can induce a transient reappearance of depressive symptoms in recovered depressed patients. The neurochemical mechanism is thought to be impairment of brain serotonin neurotransmission, but the neuropsychologic mechanisms underlying the effect are unclear. METHODS: To assess whether low-dose tryptophan depletion can tease out the psychological mechanisms sensitive to substrate depletion in vulnerable subjects without inducing mood changes, a between-subjects randomized design was used. Recovered depressed patients (n = 24) and healthy volunteers (n = 24) were administered while fasting either a tryptophan-free or a control mixture, containing 31.2 and 33.2 g of amino acids, respectively. Objective and subjective ratings of mood were made before and 5 hours after ingestion; at the latter time point, cognitive and emotional processing were also assessed. RESULTS: Low-dose tryptophan depletion did not affect mood. Significant changes in emotional and cognitive processing occurred in the recovered depressed group, however, and to a lesser extent in the healthy volunteers. The profile of effects seen in the recovered patients suggested a return of the impairments seen in acute depression. CONCLUSIONS: Our data suggest that low-dose tryptophan depletion permits investigation of the cognitive correlates of acute reductions in brain serotonin in populations vulnerable to depression and in healthy volunteers, without causing depressive symptoms.     

Patients with a major depressive episode responding to treatment with repetitive transcranial magnetic stimulation (rTMS) are resistant to the effects of rapid tryptophan depletion

Repetitive transcranial magnetic stimulation (rTMS) appears to be efficacious in the treatment of major depression based on the results of controlled studies, but little is known about its antidepressant mechanism of action. Mood sensitivity following rapid tryptophan depletion (RTD) has been demonstrated in depressed patients responding to SSRI antidepressants and phototherapy, but not in responders to electroconvulsive therapy (ECT). We sought to study the effects of RTD in patients with major depression responding to a course of treatment with rTMS. Twelve subjects treated successfully with rTMS monotherapy underwent both RTD and sham depletion in a double-blind crossover design. Depressive symptoms were assessed using both a modified Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). The differential change in depression scores across the procedures was compared. No significant difference in mood symptoms was noted between RTD and the sham-depletion procedure on either continuous measures of depression, or in the proportions of subjects that met predefined criteria for a significant degree of mood worsening. Responders to rTMS are resistant to the mood perturbing effects of RTD. This suggests that rTMS does not depend on the central availability of serotonin to exert antidepressant effects in major depression.     

Treatment of severe depression with the selective serotonin reuptake inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are recognized as effective as and better tolerated than older antidepressant therapies and have become the drugs of choice in the treatment of mild to moderate depression. However, there is a clinical impression that the SSRIs are less effective than older therapies in the severely depressed patient. A limited number of trials have attempted to address this issue. This review assesses 16 controlled studies of SSRIs in severe depression. The findings from a majority of studies found the SSRIs to be superior to placebo and as effective as but better tolerated than the tricyclic antidepressants (TCAs) in severely depressed patients. Although future studies are needed to corroborate and elaborate on these data, studies still support the use of SSRIs in this patient population. Depression and Anxiety 4:182–189, 1996/1997. © 1997 Wiley-Liss, Inc.     

Serotonergic‘vulnerability’ in affective disorder: a study of the tryptophan depletion test and relationships between peripheral and central serotonin indexes in citalopram-responders

A double-blind study of the tryptophan depletion (TD) challenge was performed on a sample consisting of 20 patients with a major depressive disorder in clinical remission after citalopram treatment. TD was induced by the intake of 43 g of an amino acid mixture containing the five large neutral amino acids. The control group received the same mixture, to which 2.3 g tryptophan had been added. Five of the 12 challenged patients showed a worsening of depressive symptoms during the day of the test. In contrast, there was no mood alteration in the eight control patients. Baseline Cortisol levels were significantly higher in responders to TD compared to those in non-responders and controls. Platelet serotonin-receptor function and plasma prolactin levels were correlated. There was a significant positive correlation in the baseline data between rated mood state and plasma Cortisol and a significant inverse correlation between related mood state and plasma tryptophan concentration. Thus low mood appeared to be associated with low serotonin precursor availability as well as with high Cortisol levels.     

Effect of tryptophan depletion on smokers and nonsmokers with and without history of major depression.

BACKGROUND: Serotonergic dysregulation is posited to contribute to comorbidity between nicotine dependence and depression. We tested whether acute tryptophan depletion (ATD) triggers depressive symptoms in euthymic, unmedicated smokers and nonsmokers with and without history of major depressive disorder (MDD). METHODS: Acute tryptophan depletion and taste-matched placebo challenges were administered double-blind in counter-balanced order. Participants were four groups of volunteers hypothesized to be of increasing affective vulnerability as follows: nonsmokers lacking recurrent personal and familial history of MDD (n = 20), smokers lacking recurrent personal and familial history of MDD (n = 21), nonsmokers with history of recurrent personal and familial MDD (n = 16), and smokers with recurrent personal and familial history of MDD (n = 16). Depression, dysphoric mood, and plasma amino acids were measured at baseline and around the time of peak depletion. RESULTS: Depressive symptom response to ATD was heightened significantly by history of MDD (p < .001) and marginally by smoking (p = .09). Smoking seemed to magnify the ATD response of those with a history of MDD (effect size = .63) but had no effect on those without MDD history (effect size = .06). CONCLUSIONS: Depressive symptom response to serotonergic challenge is exaggerated in unmedicated, euthymic adults with recurrent personal and familial vulnerability to MDD, perhaps especially if they also smoke.     

Are there differences in the symptoms that respond to a selective serotonin or norepinephrine reuptake inhibitor?

BACKGROUND: We examined two previously published studies comparing a norepinephrine (NE) selective agent, reboxetine, and a serotonin (5-HT) selective agent, fluoxetine, to determine if these agents have different effects on individual depressive symptoms. METHODS: Both studies were 8-week, double-blind, comparison studies of men and women with DSM III-R major depression. Within-group effect sizes for individual symptom change on the Hamilton Depression Rating Scale (HAMD) were determined in the observed case samples and in patients for whom the symptom was relatively severe at baseline. We required that any significant differences in one sample be cross-validated in the second. RESULTS: Two hundred fifty-three subjects in study I and 168 subjects in study II were randomized to reboxetine or fluoxetine. In both samples, depressed mood, decreased interest, and psychic anxiety had the greatest change. Effect sizes for all HAMD symptoms were similar for the two drugs. No difference between groups in one sample was replicated in the second. Among subjects with severe symptoms, no significant differences were cross-validated. CONCLUSIONS: Reboxetine and fluoxetine appear to have similar effects on depressive symptoms. These data suggest that NE and 5-HT selective antidepressant drugs act through the same final common pathway and challenge the belief that symptom differences are useful for antidepressant selection.     

Tryptophan depletion and serotonin loss in selective serotonin reuptake inhibitor-treated depression: an [(18)F] MPPF positron emission tomography study.

BACKGROUND: Recurrence of depressive symptoms after tryptophan depletion (TD) in selective serotonin reuptake inhibitor (SSRI)-treated depression is an important, unexplained phenomenon. With [(18)F] MPPF positron emission tomography (PET), serotonin (5-hydroxytryptamine, 5-HT) 1A receptor binding potential (5-HT(1A)BP) was measured after TD in various brain regions in citalopram-treated depression. This 5-HT(1A)BP measurement is sensitive to changes in extracellular 5-HT in animal models. METHODS: Eight remitted patients with major depressive disorder received [(18)F] MPPF PET scans twice: once after TD and once after sham depletion. Behavioral measures were evaluated with the Hamilton Depression Rating Scale and visual analog scales. RESULTS: No effect on regional 5-HT(1A)BP was observed after TD, despite an 86% decrease in total plasma tryptophan and transient depressive relapse in six of eight patients. CONCLUSIONS: Large-magnitude changes in extracellular 5-HT are not crucial for the mood effects observed in SSRI-treated subjects after TD. Therefore, greater consideration must be given to other mechanisms that involve vulnerability to small perturbations in extracellular 5-HT, such as impairment of signal transduction.     

Acute tryptophan depletion increases experimental nausea but also induces hunger in healthy female subjects

Background Acute tryptophan depletion (ATD) is an experimental model to reduce central serotonin levels. Methods Thirty‐eight healthy female subjects were randomly assigned to two groups (ATD and control) in a randomized, double‐blinded parallel‐group design. Following a standardized and balanced amino acid diet (including 1.21 g tryptophan) on the first day, they received either a protein drink without tryptophan (but substituted by other amino acids) (ATD condition) or the balanced protein drink with tryptophan (control condition) 24 h later. Four hours after its consumption, they were exposed to a standard rotation procedure. Symptom ratings (SR), ratings of hunger and mood scores were taken prior to rotation, at each break, and 15 and 30 min thereafter, together with saliva cortisol samples. Key Results Five subjects could not tolerate the entire rotation procedure and were excluded from analysis. For the remaining n = 33, SR and hunger ratings were higher during ATD than during control conditions, but mood was unaffected. Cortisol levels rose significantly with rotation but were unaffected by ATD. High baseline cortisol levels were associated with lower SR during rotation. The protective effects of morning cortisol were pronounced during the menstrual and follicular phase of the cycle and not present during ovulation and the luteal phase. Conclusions & Inferences Acute tryptophan depletion is associated with increased symptoms of nausea in healthy female subjects when exposed to body rotation. Acute tryptophan depletion also increases hunger rating. These opposite effects may indicate independent actions of the serotonin on central and peripheral functions.     

Oscillatory serotonin function in depression

Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors and associated central nervous system activities are altered in depression. Recent data suggest that ultradian rhythms in serotonin (5HT) function also change in depression. In two separate studies, 5HT metabolites in cerebrospinal fluid (CSF) were measured every 10 min for 24 h before and after chronic antidepressant treatment. Antidepressant treatments were associated with enhanced ultradian amplitudes of CSF metabolite levels. Another study used resting‐state functional magnetic resonance imaging (fMRI) to measure amplitudes of dorsal raphé activation cycles following sham or active dietary depletions of the 5HT precursor (tryptophan). During depletion, amplitudes of dorsal raphé activation cycles increased with rapid 6 s periods (about 0.18 Hz) while functional connectivity weakened between dorsal raphé and thalamus at slower periods of 20 s (0.05 Hz). A third approach studied MDMA (ecstasy, 3,4‐methylenedioxy‐N‐methylamphetamine) users because of their chronically diminished 5HT function compared with non‐MDMA polysubstance users (Karageorgiou et al., 2009). Compared with a non‐MDMA using cohort, MDMA users showed diminished fMRI intra‐regional coherence in motor regions along with altered functional connectivity, again suggesting effects of altered 5HT oscillatory function. These data support a hypothesis that qualities of ultradian oscillations in 5HT function may critically influence moods and behaviors. Dysfunctional 5HT rhythms in depression may be a common endpoint and biomarker for depression, linking dysfunction of slow brain network oscillators to 5HT mechanisms affected by commonly available treatments. 5HT oscillatory dysfunction may define illness subtypes and predict responses to serotonergic agents. Further studies of 5HT oscillations in depression are indicated. Synapse 67:801–820, 2013 . © 2013 Wiley Periodicals, Inc.     

西酞普兰合并认知疗法治疗脑卒中后抑郁的疗效观察

目的了解西酞普兰合并认知疗法治疗脑卒中后抑郁的疗效。方法将64例脑卒中后抑郁患者随机分为研究组和对照组,研究组给予西酞普兰合并认知疗法,对照组单独用西酞普兰治疗,疗程12周。用汉密顿抑郁量表（HAMD）、不良反应量表（TESS）分别评定疗效和不良反应。结果在治疗第4,8及12周后,研究组上述治疗时段的HAMD评分均分别明显低于对照组;临床疗效研究组优于对照组（U=2．10,P〈0．05）;两组药物不良反应元显著性差异（P〉0．05）。结论西酞普兰合并认知疗法治疗脑卒中后抑郁的疗效较好。     

Differential effects of tryptophan depletion on emotion processing according to face direction

Reading facial emotion is disrupted by both psychopathology,such as autism, and altered function of neurotransmitter, suchas serotonin. These effects could result from reduced sensitivityof emotional processing systems to facial emotion. The impactof facial expression is also greater when personally directedthan when averted. We therefore hypothesized that brain activityassociated with emotional representation, would be more susceptibleto manipulation of serotonin function by Acute Tryptophan Depletion(ATD) for front-viewed than side-viewed faces, measured usingfunctional imaging (fMRI). ATD reduced activity independentof face view in left superior temporal sulcus (STS) and anteriorcingulate. In temporal pole, medial frontal cortex and orbitofrontalcortex, ATD also reduced activity, but specifically for front-viewedfaces. In right STS, ATD increased activity, but specificallyfor side-viewed faces. Activity in the amygdalae depended onface view and emotion type. We suggest that engagement of empathicand associative learning functions when viewing faces is facilitatedby direct facial view and intact serotonin transmission. Avertedfaces, and reduced serotonin function facilitate attention tothe external goal of gaze. These changes could be adaptive ina threatening context and markedly affect empathic functionin conditions associated with impaired serotonin function, suchas depression and autism.     

奥卡西平联合选择性5-羟色胺再摄取抑制剂治疗激越性抑郁的开放性研究

目的 观察和评价门诊32例激越性抑郁患者在应用选择性5-羟色胺再摄取抑制剂(SSRI)的基础上联合应用奥卡西平的效果与不良反应.方法 对符合抑郁症诊断标准同时伴有激越症状的32例患者在应用SSRI的基础上联合应用奥卡西平(0.3 g/片,第1、2天1片,第3天起2片,7 d内根据情况用至4～5片)治疗,观察8周,应用汉密尔顿抑郁评定量表(HAMD)、汉密尔顿焦虑评定量表(HAMA)、杨氏躁狂评定量表(YMRS)评价疗效和不良反应.结果 32例患者奥卡西平平均用量为(1020±65)mg/d.临床有效率为87.5%(28/32),痊愈率为65.6%(21/32).治疗后1周、2周、4周、8周的有效率和痊愈率分别是28.1%(9/32)与6.3%(2/32)、37.5%(12/321与12.5%(4/32)、46.9%05/32)与31.3%(10/32)、90.6%(29/32)与65.6%(21/32).患者治疗后1周、2周、4周、8周的各量表评分与治疗前比较差异均有统计学意义(P<0.05).32例患者中没有1例出现转躁狂现象.结论 奥卡西平联合SSRI治疗激越性抑郁可获得较好的疗效.     

Effects of tryptophan depletion and catecholamine depletion on immune parameters in patients with seasonal affective disorder in remission with light therapy.

BACKGROUND: Altered immunologic parameters are found in symptomatic depressed patients relative to remitted depressed patients and healthy controls. We investigated whether tryptophan depletion and catecholamine depletion induce alterations in immunologic parameters in patients with seasonal affective disorder remitted on light therapy, and whether these changes are associated with changes in mood. METHODS: Remitted patients with seasonal affective disorder underwent tryptophan depletion, catecholamine depletion, and sham depletion in a prospective randomized, double-blind crossover design. Measures of depression, plasma levels of tryptophan and catecholamine metabolites, and plasma levels of cytokines (sIL-4, IL-6, neopterin, sTNF-R1 and sTNF-R2) were obtained at baseline, and 7, 24, and 30 hours after monoamine depletion. RESULTS: Tryptophan depletion decreased plasma total and free tryptophan levels; catecholamine depletion decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels. Tryptophan depletion and catecholamine depletion, but not sham depletion, induced a transient exacerbation of depressive symptoms (p <.001); plasma neopterin levels increased during tryptophan depletion and catecholamine depletion (p <.05). Tryptophan depletion and catecholamine depletion induced a transient reduction of plasma sIL-4 levels (p <.05). A significant correlation was found between sIL-4R levels and depression ratings after tryptophan depletion (r = -.61, p <.05). CONCLUSIONS: The monoamine depletion-induced alterations of humoral and cellular immunity suggest a potential role of immunologic parameters in the pathophysiology of seasonal affective disorder; however, the results must be considered preliminary and require further study.     

Self-poisonings with tricyclic antidepressants and selective serotonin reuptake inhibitors in Tehran,Iran

In a prospective hospital-based cohort study, we addressed the question of severity and outcome of antidepressant poisonings in patients who attended the Loghman-Hakim Hospital Poison Center, the only national center in Tehran dedicated for detoxification. The aim of the study was to find out if tricyclic antidepressant (TCA) intoxications require more therapeutic efforts than selective serotonin reuptake inhibitor (SSRI) intoxications. The study was applied over a 7-week period (28 March–20 May 2006). From 3578 intoxications, 334 patients with antidepressant or lithium self-poisoning were identified (9.3% of all poisoning cases; 233 females, 101 males; median age 24 years, min 13, max 70). Compared to SSRI single-substance intoxications (n=17), TCA single-substance intoxications (n=73) were associated with: (1) a significantly lower level of consciousness (P=0.005); (2) a significantly higher admission frequency (80.8 vs. 35.3%; P<0.001); and (3) a higher intubation frequency (13.7 vs. 0%; P=ns). SSRI multiple-substance intoxications were associated with a significantly lower level of consciousness than SSRI single-substance intoxications (P=0.042), while there was no significant difference between TCA multiple- and single-substance intoxications. This study suggests that an overdose with SSRIs results in a more favourable clinical outcome than an overdose with TCAs.     

文拉法辛缓释剂替换治疗门诊抑郁症患者观察

目的:了解文拉法辛缓释剂替换选择性5-羟色胺再摄取抑制剂类(SSRIs)疗效欠佳的门诊抑郁症患者的有效性和安全性. 方法:将符合抑郁症诊断标准并经氟西汀,舍曲林,氟伏沙明和西酞普兰4种SSRIs抗抑郁剂之一治疗量治疗6周而疗效不佳的抑郁症患者72例随机分为两组.文拉法辛组34例换用文拉法辛缓释剂,帕罗西汀组38例换用帕罗西汀,疗程6周.换药前均停原用SSRIs药物.以汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)、临床疗效总评量表病情严重程度(CGI-SI)分别于入组时、治疗2周末、4周末、6周末评定疾病的严重程度及好转情况;以治疗中出现的症状量表(TESS)评定药物的不良反应. 结果:两组在治疗4周末及6周末时其HAMD、CGI-SI评分差异有显著性,HAMA评分则从治疗2周末起即表现出显著性差异.文拉法辛组疗效优于帕罗西汀组,两组显效率分别为70.6%和52.6%,不良反应发生率无明显差异. 结论:文拉法辛缓释剂替换经SSRIs抗抑郁剂治疗效差的门诊抑郁症患者可取得好的疗效,且安全性好.     

Cost-effectiveness of cognitive behavioural therapy and selective serotonin reuptake inhibitors for major depression in children and adolescents

OBJECTIVE: To assess from a health sector perspective the incremental cost-effectiveness of cognitive behavioural therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) for the treatment of major depressive disorder (MDD) in children and adolescents, compared to "current practice". METHOD: The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analysis of randomised controlled trials. An assessment on second stage filter criteria ("equity", "strength of evidence", "feasibility" and "acceptability to stakeholders") is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are tracked for the duration of a new episode of MDD arising in eligible children (age 6-17 years) in the Australian population in the year 2000. Simulation-modelling techniques are used to present a 95% uncertainty interval (UI) around the cost-effectiveness ratios. RESULTS: Compared to current practice, CBT by public psychologists is the most cost-effective intervention for MDD in children and adolescents at A$9000 per DALY saved (95% UI A$3900 to A$24 000). SSRIs and CBT by other providers are less cost-effective but likely to be less than A$50 000 per DALY saved (> 80% chance). CBT is more effective than SSRIs in children and adolescents, resulting in a greater total health benefit (DALYs saved) than could be achieved with SSRIs. Issues that require attention for the CBT intervention include equity concerns, ensuring an adequate workforce, funding arrangements and acceptability to various stakeholders. CONCLUSIONS: Cognitive behavioural therapy provided by a public psychologist is the most effective and cost-effective option for the first-line treatment of MDD in children and adolescents. However, this option is not currently accessible by all patients and will require change in policy to allow more widespread uptake. It will also require "start-up" costs and attention to ensuring an adequate workforce.