Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder.

UNLABELLED: Major depressive disorder (MDD) is often accompanied by significant cognitive impairment, and there are limited interventions specific to this particular symptom. S-adenosylmethionine (SAMe), a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism, is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD. OBJECTIVES: This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD. METHODS: Forty-six serotonin-reuptake inhibitor (SRI) non-responders with MDD enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe were administered the self-rated cognitive and physical symptoms questionnaire (CPFQ), a validated measure of cognitive as well as physical symptoms of MDD, before and after treatment. RESULTS: There was a greater improvement in the ability to recall information (P=0.04) and a trend towards statistical significance for greater improvement in word-finding (P=0.09) for patients who received adjunctive SAMe than placebo. None of the remaining five items reached statistical significance. CONCLUSIONS: These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients, and warrant replication.

SAMe and sexual functioning.

BACKGROUND: Sexual dysfunction is a known side effect of antidepressant treatment (ADT), affecting up to 58-73% of those who receive ADT, potentially affecting antidepressant adherence. Consequently, it is vital to develop novel treatments that target antidepressant-induced sexual dysfunction. METHODS: We examined whether adjunctive S-adenosyl-l-methionine (SAMe) is associated with greater improvement in sexual functioning than adjunctive placebo by measuring changes in sexual functioning using the Massachusetts General Hospital-Sexual Functioning Questionnaire (MGH-SFQ) during a 6-week, single-center, randomized, double-blind trial of SAMe augmentation for SSRI/SNRI- nonresponders. RESULTS: Controlling for the degree of arousal dysfunction at baseline as well as the degree of change in HDRS-17 scale scores during the course of the study, men treated with adjunctive SAMe demonstrated significantly lower arousal dysfunction at endpoint than those treated with adjunctive placebo. In addition, controlling for the degree of erectile dysfunction at baseline as well as the degree of change in HDRS-17 scale scores, men treated with adjunctive SAMe demonstrated significantly lower erectile dysfunction at endpoint than those treated with adjunctive placebo. CONCLUSIONS: In the present study, we have observed that adjunctive SAMe can have positive benefit on male arousal and erectile dysfunction, independent of improvement in depressive symptoms. These findings are preliminary, and warrant replication. CLINICAL TRIALS.GOV IDENTIFIER: NCT00093847; titled 'Optimizing the Effectiveness of Selective Serotonin Reuptake Inhibitors (SSRIs) in Treatment-Resistant Depression', accessible at: http://clinicaltrials.gov/ct2/show/NCT00093847.

Pretreatment frontal EEG and changes in suicidal ideation during SSRI treatment in major depressive disorder.

OBJECTIVE: We investigated frontal quantitative EEG (QEEG) as predictor of changes in suicidal ideation (SI) during SSRI treatment in major depressive disorder (MDD). METHOD: Eighty-two subjects meeting DSM-IV criteria for MDD entered an 8-week, prospective, open-label treatment with flexible dose SSRIs and completed at least 4 weeks of treatment. We assessed MDD severity with the 17-item Hamilton Depression Rating Scale (HAM-D-17); change in SI was measured with HAM-D item no. 3. We recorded four-channel EEGs (F7-Fpz, F8-Fpz, A1-Fpz, A2-Fpz) before treatment. RESULTS: During the first 4 weeks of treatment 9 (11%) subjects experienced worsening SI. Left-right asymmetry of combined theta + alpha power correlated significantly with change in SI from baseline, even when adjusting for changes in depression severity (HAM-D-17) and for the SSRI utilized. CONCLUSION: Frontal QEEG parameters before treatment may predict worsening SI during SSRI treatment in MDD.

Preadult onset vs. adult onset of major depressive disorder: a replication study.

OBJECTIVE: In the first 1500 participants with major depressive disorder (MDD) that entered the sequenced treatment alternatives to relieve depression (STAR*D) study, those with preadult onset MDD were more likely to be women and to have a more chronic, severe and disabling form of depression than those with adult onset MDD. This study seeks to replicate these findings. METHOD: The second wave of STAR*D enrollees included 2541 out-patients with MDD, divided into preadult (before age 18) and adult (age 18 or later) onset groups. RESULTS: Participants with a preadult onset of MDD (38%) were younger, ill for longer and more likely to be women than those with adult onset MDD (62%). After adjusting for age, duration of illness and gender, participants with preadult onset MDD also had higher rates of family history of depression, more past suicide attempts, and lower rates of obsessive compulsive and panic disorder. CONCLUSION: Preadult onset MDD may be associated with a more familial form of depression with more suicidality than adult onset MDD.

Continuation cognitive-behavioural therapy maintains attributional style improvement in depressed patients responding acutely to fluoxetine.

BACKGROUND: Little is known about how continuation and maintenance cognitive-behavioural therapy (CBT) influences important psychological constructs that may be associated with long-term outcome of major depressive disorder. The goal of this study was to examine whether CBT would help maintain attributional style changes experienced by patients during acute phase fluoxetine treatment. METHOD: Three hundred and ninety-one patients with major depressive disorder were enrolled in an open, fixed-dose 8 week fluoxetine trial. Remitters to this acute phase treatment (N= 132) were randomized to receive either fixed-dose fluoxetine (meds only) or fixed-dose fluoxetine plus cognitive-behavioural therapy (CBT+meds) during a 6-month continuation treatment phase. The Attributional Style Questionnaire (ASQ) was completed by patients at three time points - acute phase baseline, continuation phase baseline and continuation phase endpoint. Analysis of covariance was used to compare continuation phase ASQ composite score changes between groups. RESULTS: Patients in both treatment groups experienced significant gains in positive attributional style during the acute phase of treatment. Continuation phase ASQ composite change scores differed significantly between treatment groups, with the CBT + meds group maintaining acute phase positive attributional style changes, and the meds only group exhibiting a worsening of attributional style. The two treatment groups did not significantly differ in rates of relapse and final continuation phase visit HAMD-17 scores. CONCLUSIONS: In this sample, the addition of CBT to continuation psychopharmacological treatment was associated with maintenance of acute treatment phase attributional style gains. Further research is needed to evaluate the role of such gains in the long-term course of depressive illness.

Personality disorders and depression.

BACKGROUND: Personality disorders (PDs) were assessed among depressed out-patients by clinical interview before and after antidepressant treatment with fluoxetine to assess the degree of stability of PD diagnoses and determine whether changes in PD diagnoses across treatment are related to the degree of improvement in depressive symptoms. METHOD: Three hundred and eighty-four out-patients (55% women; mean age = 39.9 +/- 10.5) with major depressive disorder (MDD) diagnosed with the SCID-P were enrolled into an 8 week trial of open treatment with fluoxetine 20 mg/day. The SCID-II was administered to diagnose PDs at baseline and endpoint. RESULTS: A significant proportion (64%) of our depressed out-patients met criteria for at least one co-morbid personality disorder. Following 8 weeks of fluoxetine treatment, there was a significant reduction in the proportion of patients meeting criteria for avoidant, dependent, passive-aggressive, paranoid and narcissistic PDs. From baseline to endpoint, there was also a significant reduction in the mean number of criteria met for paranoid, schizotypal, narcissistic, borderline, avoidant, dependent, obsessive-compulsive, passive aggressive and self-defeating personality disorders. While changes in cluster diagnoses were not significantly related to improvement in depressive symptoms, there were significant relationships between degree of reduction in depressive symptoms (percentage change in HAM-D-17 scores) and degree of change in the number of criteria met for paranoid, narcissistic, borderline and dependent personality disorders. CONCLUSIONS: Personality disorder diagnoses were found to be common among untreated out-patients with major depressive disorder. A significant proportion of these patients no longer met criteria for personality disorders following antidepressant treatment, and changes in personality disorder traits were significantly related to degree of improvement in depressive symptoms in some but not all personality disorders. These findings suggest that the lack of stability of PD diagnoses among patients with current MDD may be attributable in part to a direct effect of antidepressant treatment on behaviours and attitudes that comprise PDs.

Use of the five-factory inventory in characterizing patients with major depressive disorder.

Research on personality traits has suggested an association between depression and certain personality traits, such as neuroticism and extraversion. Costa and McCrae's five-factor personality inventory (NEO) has been shown to measure personality traits in a nonclinical population, but its use has not been fully explored in clinical populations. This study aims to compare NEO results in a sample of depressed outpatients with published test norms, and determine if different levels of neuroticism and extraversion are associated with differences in certain psychosocial and clinical characteristics. Seventy-six depressed outpatients participating in antidepressant clinical trials completed this self-report questionnaire before beginning pharmacological treatment. Diagnosis of major depressive disorder (MDD) was made using the Structured Clinical Interview for DSM-III-R or DSM-IV and the severity of depression was measured with the 17-item Hamilton Depression Rating Scale (HAM-D). The three analyses conducted were as follows: (1) NEO factor scores were compared with published normative means; (2) three groups, based on level of neuroticism, were compared on certain psychosocial and clinical characteristics; and (3) three groups, based on level of extraversion, were compared on the same psychosocial and clinical characteristics. Both the males and females obtained T score values for the Neuroticism Scale 1.5 SD above the mean, for the Extraversion Scale 1.5 SD below the mean, and for the Conscientiousness Scale 1.5 SD below the mean. No significant differences were found between subjects with different levels of neuroticism and extraversion, although a trend did exist indicating a positive relationship between neuroticism and severity of depression. Depressed outpatients experience frequent negative affects, have irrational thought processes, cope with stress poorly, have difficulty controlling impulses, prefer to be alone, and have difficulty carrying out tasks. Future studies should examine how such personality factors affect response to treatment and course of illness.

Tryptophan depletion in SSRI-recovered depressed outpatients.

RATIONALE: Recently, a number of studies have challenged the finding that acute tryptophan depletion (TD) increases depressive symptoms in medicated, formerly depressed patients. The present study examined the effects of acute nutritional TD on remitted depressed patients currently treated with selective serotonin reuptake inhibitors. In an attempt to clarify conflicting earlier findings, the effects of a number of clinical variables on outcome were also investigated. METHODS: Ten patients underwent TD in a double-blind, controlled, balanced crossover fashion. The control session followed the procedure of Krahn et al. (1996 Neuropsychopharmacology 15:325-328). Sessions were 5-8 days apart. RESULTS: TD was significantly related to increased scores on clinician-rated depression and anxiety scales, and on self-rated depression, anxiety, and somatic symptoms. The control challenge had no effect, despite the fact that the reductions in plasma tryptophan during the control session were unexpectedly high. Some evidence was found for a threshold in the relationship between reduction of plasma tryptophan and mood response. CONCLUSIONS: The mood effect of TD in medicated, formerly depressed patients was confirmed. A threshold may exist for mood effects following TD, implying that recent negative findings may have been caused by insufficient depletion. No other predicting or mediating factors were identified, although the variable "history of response pattern to medication" deserves further study.

Management of major depression in the primary care setting.

BACKGROUND: Patients treated in community clinics, particularly those of minority status, may rely more heavily on primary care physicians (PCPs) for the diagnosis and management of depression. We wished to determine how PCPs in a community clinic setting initially manage patients newly diagnosed with major depression. METHODS: 698 patients were screened for major depression by the Structural Clinical Interview for DSM-III-R in a community-based primary care health center. Forty outpatients (29 Hispanic) were found to suffer from major depression. A letter explaining positive findings was sent to the patients' PCPs. Medical record charts were reviewed 3 months later to determine the PCP's management following the diagnosis. RESULTS: Of the 38 patients who remained in the study at 3 months, 20 (53%) received no intervention from the PCP by the end of 3 months after diagnosis, and of these, 14 were Hispanic. Five (13%) were prescribed an antidepressant by the PCP. Nine (24%) were referred to mental health services for medication, psychotherapy or combination treatment. Four (11%) were prescribed an antidepressant and then referred to mental health services. Differences between management of Hispanic and non-Hispanic patients were not statistically significant. CONCLUSIONS: Independent screening by psychiatrists in primary care settings may not be adequate enough to ensure appropriate management of depression by PCPs. Possible explanations may include time constraints during primary care visits, patient and/or physician reticence, and insufficient education of PCPs about depression.

T3 blood levels and treatment outcome in depression.

OBJECTIVE: We examined the correlation between the basal triiodothyronine resin uptake (T3-RU) levels in depressed subjects and the response to anti-depressant treatment. METHOD: We treated with fluoxetine 235 outpatients meeting DSM-IV criteria for major depression. We measured T3 resin uptake (T3-RU) levels before the onset of treatment. The 17-item Hamilton Rating Scale for Depression (Ham-D-17) was administered before, during and after the eight weeks of treatment to assess changes in depressive symptoms. RESULTS: 16 patients (6.8 percent) had low T3-RU levels (range 16.5-21), and 7 patients (3.0 percent) had high T3-RU levels (range 36-38). No relationship was found between T3-RU levels and clinical improvement, defined as either total Ham-D-17 score change or Ham-D-17 score < or = 7 in the last 3 weeks of treatment, even after adjusting for baseline severity of depression. CONCLUSION: Abnormal T3-RU levels are rather uncommon in outpatient depression and do not correlate with the response to antidepressant treatment or lack thereof.

Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression.

BACKGROUND: Folate and B12 deficiencies may result in macrocytic anemia, and are common in major depression; hypofolatemia may result in poorer antidepressant response. We wished to determine whether anemia or macrocytosis predict hypofolatemia, low B12, or refractoriness to antidepressants. METHODS: After obtaining serum folate, B12, and hematological indices, 213 depressed adults were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was measured. RESULTS: Neither macrocytosis nor anemia predicted low serum folate/B12, or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12, none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders, 3% had macrocytosis; 24% had low HCT; 25% had low RBC. CONCLUSION: Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants. Measurement of folate and B12 should be considered when evaluating treatment refractoriness.

Timing of onset of antidepressant response with fluoxetine treatment.

OBJECTIVE: The purpose of this study was to assess the time until onset of antidepressant response with fluoxetine treatment. METHOD: The authors evaluated 182 outpatients with major depression who had a sustained acute response to fluoxetine treatment. The outpatients received 8 weeks of treatment with 20 mg/day of fluoxetine and were assessed biweekly with the 17-item Hamilton Depression Rating Scale. The onset of response was defined as a 30% decrease in score on the Hamilton depression scale that persisted and led to a 50% decrease by week 8. The Kaplan-Meier product limit and Cox regression analysis were used to model the relationship between relevant variables and time until onset of response. RESULTS: The authors found that at weeks 2, 4, and 6, the probabilities of having an onset of response (for responders) were 55.5%, 24.7%, and 9.3%, respectively. The cumulative probabilities of onset of response at each time point were 55.5%, 80.2%, and 89.5%. Neither demographics nor clinical characteristics of depression predicted time until initial response. CONCLUSIONS: These data suggest that more than half of eventual responders to fluoxetine treatment at 8 weeks start to respond by week 2; over 75% start to respond by week 4. Conversely, the lack of onset of response at 4-6 weeks was associated with about a 73%-88% chance that patients would not have an onset of response by 8 weeks.

Fenfluramine challenge in unipolar depression with and without anger attacks.

We have previously hypothesized that patients with major depression and anger attacks may have a greater central serotonergic dysregulation than depressed patients without such attacks. We wanted to compare the prolactin response to fenfluramine challenge, as an indirect measure of central serotonergic function, in depressed patients with and without anger attacks. We recruited 37 outpatients (22 men and 15 women; mean age: 39.5+/-10.5) with DSM-III-R major depressive disorder, diagnosed with the SCID-P. Their initial 17-item Hamilton Rating Scale for Depression score was >/=16. Patients were classified as either having or not having anger attacks with the Anger Attacks Questionnaire. All patients received a single-blind placebo challenge followed by a fenfluramine challenge (60 mg orally) the next day. Plasma prolactin measurements were obtained with double antibody radioimmunoassay before and after both placebo and fenfluramine challenges, and fenfluramine and norfenfluramine blood levels after each challenge were determined by gas chromatography. Of the 37 study participants, 17 (46%) were classified as having anger attacks. There were no significant differences in age, gender, fenfluramine, or norfenfluramine blood levels between depressed patients with and without anger attacks. Depressed patients with anger attacks showed a significantly blunted prolactin response to fenfluramine challenge compared to patients without anger attacks. As previous studies have shown blunted prolactin responses to fenfluramine in impulsive aggression among patients with personality disorders, our results support our hypothesis that depressed patients with anger attacks may have a relatively greater serotonergic dysregulation than depressed patients without these attacks.

Anxiety disorders in major depression.

The prevalence and clinical impact of anxiety disorder comorbidity in major depression were studied in 255 depressed adult outpatients consecutively enrolled in our Depression Research Program. Comorbid anxiety disorder diagnoses were present in 50.6% of these patients and included social phobia (27.0%), simple phobia (16.9%), panic disorder (14.5%), generalized anxiety disorder ([GAD] 10.6%), obsessive-compulsive disorder ([OCD] 6.3%), and agoraphobia (5.5%). While both social phobia and generalized anxiety preceded the first episode of major depression in 65% and 63% of cases, respectively, panic disorder (21.6%) and agoraphobia (14.3%) were much less likely to precede the first episode of major depression than to emerge subsequently. Although comorbid groups were not distinguished by depression, anxiety, hostility, or somatic symptom scores at the time of study presentation, patients with comorbid anxiety disorders tended to be younger during the index episode and to have an earlier onset of the major depressive disorder (MDD) than patients with major depression alone. Our results support the distinction between anxiety symptoms secondary to depression and anxiety disorders comorbid with major depression, and provide further evidence for different temporal relationships with major depression among the several comorbid anxiety disorders.

Depressive breakthrough.

Controlled studies of continuation and maintenance pharmacotherapy have consistently shown the advantage of drug therapy over placebo for the prevention of relapses and recurrences, particularly when antidepressant medications are maintained at the full dose required initially to establish remission. Nevertheless, controlled and observational studies indicate substantial rates of relapse and recurrence despite long-term treatment. Although depressive breakthrough is a common clinical problem, few uncontrolled studies and no controlled trials are available on management of depressive breakthrough. Three principal pharmacologic strategies seem to be (1) increasing dose, (2) adding another agent, and (3) switching antidepressants. Controlled studies of long-term treatment are needed to identify the optimal nature and sequence of approaches for re-emergent depression and to determine what symptom severity and duration should prompt the initiation of treatment.

Compounds containing cytosolic choline in the basal ganglia: a potential biological marker of true drug response to fluoxetine.

OBJECTIVE: Studies have identified two types of antidepressant response: true drug response and placebo pattern response. This study examined the relationship between true drug response and choline-creatine ratios in the basal ganglia of depressed patients treated with fluoxetine. METHOD: The authors evaluated drug-free outpatients with major depression before (N = 41) and after (N = 15) 8 weeks of fluoxetine treatment, 20 mg/day, by using proton magnetic resonance spectroscopy. RESULTS: There was a significant difference in the degree of change from baseline to week 8 in choline-creatine ratios between the true drug response group (N = 8) and the placebo pattern response/nonresponse group (N = 7); the true drug response patients had a 20% increase in choline-creatine ratios, and the placebo pattern response/nonresponse patients had a 12% decrease in choline-creatine ratios. CONCLUSIONS: These data suggest that true drug response to fluoxetine treatment in depression may be associated with an increase in choline-creatine ratios in the basal ganglia.

Efficacy of fluvoxamine in the treatment of major depression with comorbid anxiety disorders.

BACKGROUND: Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared with major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in depressive symptoms and anxiety levels in outpatients with major depression with comorbid anxiety disorder following 12 weeks of open treatment with fluvoxamine. METHOD: We enrolled 30 outpatients (mean +/- SD age = 39.4 +/- 11.3 years; 16 women and 14 men) with DSM-IV major depressive disorder accompanied by one or more current comorbid DSM-IV anxiety disorders in our study. Patients were treated openly with fluvoxamine initiated at 50 mg/day, with an upward titration to a maximum of 200 mg/day (mean +/- SD dose = 143 +/- 45 mg/day). Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales for both depression and anxiety. Intent-to-treat analysis was used to assess outcome. RESULTS: The mean +/- SD number of comorbid anxiety disorders per patient was 2.1 +/- 1.1. Following fluvoxamine treatment, the mean +/- SD HAM-D-17 score dropped from 20.2 +/- 3.3 to 1 1.0 +/- 7.0 (p < .0001). The mean +/- SD depression CGI-S score dropped from 4.0 +/- 0.6 to 2.4 +/- 1.1 (p < .0001), and the mean +/- SD anxiety CGI-S score decreased from 4.1 +/- 0.8 to 2.5 +/- 1.2 (p < .0001). Eighteen (60%) of the 30 patients had CGI-I scores < or = 2 for both anxiety and depression at endpoint, with 53% showing a > or = 50% reduction in HAM-D-17 scores at endpoint. CONCLUSION: Although preliminary, our findings suggest that fluvoxamine is effective in treating outpatients with major depression with comorbid anxiety disorder, having a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are needed, in a larger sample, to confirm our findings.

Open study of the catechol-O-methyltransferase inhibitor tolcapone in major depressive disorder.

Tolcapone is a catechol-O-methyltransferase (COMT) inhibitor that has shown efficacy in the treatment of Parkinson's disease. The authors undertook the first study on the efficacy of this COMT inhibitor in the treatment of major depressive disorder (MDD). The authors also wanted to assess the effects of tolcapone on the choline and myoinositol resonances in the left caudate and dorsolateral frontal lobe through proton magnetic resonance spectroscopy and on whole blood levels of S-adenosyl-L-methionine (SAMe). The study enrolled 21 adults (10 men and 11 women; mean age, 42.6 +/- 9.6 years) with MDD, which was diagnosed using the Structured Clinical Interview for DSM-IV, and an initial score of > or = 16 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17). Patients were then treated openly for 8 weeks with tolcapone 400 mg twice daily. Treatment efficacy was assessed with the HAM-D-17, the Clinical Global Impressions Severity (CGI-S) scale, and the Beck Depression Inventory (BDI). Among all subjects (N = 21), there were significant (p < .0001) decreases at endpoint in HAM-D-17 scores (from 19.4 +/- 2.9 to 10.7 +/- 5.5), CGI-S scores (from 3.9 +/- 0.6 to 2.4 +/- 1.1), and BDI scores (from 21.6 +/- 8.1 to 12.3 +/- 8.6). Eight patients (38%) dropped out before completing the 8-week open study because of diarrhea, elevated liver function tests, increased anxiety, and noncompliance. No significant effects were noted on choline and myoinositol resonance or on SAMe levels in whole blood before and after 2 weeks of tolcapone treatment. The preliminary results suggest that tolcapone may be a promising agent in the treatment of MDD. Furthermore, double-blind, placebo-controlled studies are necessary to confirm this impression.