Preventing depression after stroke: Results from a randomized placebo-controlled trial

OBJECTIVE: We designed this study to determine whether the daily treatment of nondepressed acute stroke patients with sertraline reduced the incidence of depression at follow-up. METHOD: 111 patients with recent stroke (< 2 weeks; International Classification of Diseases, Tenth Revision criteria) were randomly assigned to treatment with placebo (N = 56) and sertraline (N = 55, 50 mg once daily) in this double-blind, placebo-controlled 24-week clinical trial. Subjects were recruited from the 2 largest teaching hospitals of Western Australia between June 2002 and June 2004. The primary endpoint of interest was development of clinically significant depressive symptoms as assessed by a Hospital Anxiety and Depression Scale-depression subscale score of 8 or above, or as diagnosed by the treating physician during 24 weeks. RESULTS: There was no significant difference in the incidence of depressive symptoms during 24 weeks of treatment (16.7% [8/48] sertraline vs. 21.6% [11/51] placebo, rate ratio = 0.8, 95% CI = 0.3 to 2.1, p = .590). The trial medication was discontinued by 51.8% (29/56) of patients assigned placebo and 47.3% (26/55) assigned sertraline (p = .634), most often because of perceived side effects or because the treating physician introduced an antidepressant medication. CONCLUSIONS: Twenty-four-week treatment with 50 mg of sertraline once daily initiated within 2 weeks of onset of acute stroke is not a significantly more effective strategy to prevent 6-month depression than usual care plus placebo among nondepressed stroke patients. New pharmacologic and nonpharmacologic strategies need to be developed to reduce the health and financial burden associated with depression after stroke.     

Effectiveness of chromium in atypical depression: a placebo-controlled trial.

BACKGROUND: Chromium picolinate (CP) has been reported to benefit patients with symptoms of atypical depression. METHODS: A placebo-controlled, double-blind, pilot study of CP was conducted in 15 patients with DSM-IV major depressive disorder, atypical type. Patients received 600 micro g of CP or matching placebo (PBO) for 8 weeks. RESULTS: Seven (70%) CP and zero (0%) PBO patients met responder criteria (p =.02). Other outcomes were consistent with greater effect of CP. Three patients on CP failed to show any improvement. Chromium picolinate was well tolerated. CONCLUSIONS: Chromium picolinate shows promising antidepressant effects in atypical depression. Its mechanism of action may relate to 5HT2A downregulation, increased insulin sensitivity, or to other effects.     

Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial

BACKGROUND: Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings. OBJECTIVE: To test whether the addition of metyrapone to standard antidepressants induces a more rapid, more efficacious, and sustained treatment response in patients with major depression. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Hospitalized care. PATIENTS: Sixty-three inpatients with a DSM-IV diagnosis of major depression and a baseline score 18 points or higher on the Hamilton Rating Scale for Depression. INTERVENTIONS: Random allocation to 2 treatment groups receiving either placebo or metyrapone (1 g/d) for the first 3 weeks during a 5-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine). MAIN OUTCOME MEASURES: Primary outcome criteria were the number of responders and the time to onset of action. Responder rates were considered twice after 3 and 5 weeks with a definition of treatment response as 30% and 50% reduction, respectively, of baseline Hamilton Rating Scale for Depression scores. Onset of action was defined as the time point at which at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores occurred. RESULTS: Using intention-to-treat analysis, we found that a higher proportion of patients receiving metyrapone showed a positive treatment response at day 21 (23 of 33 patients) and at day 35 (19 of 33 patients) compared with placebo patients (day 21: 13 of 30 patients; Fisher exact P = .031; day 35: 10 of 30 patients; Fisher exact P = .047). The clinical course of patients treated with metyrapone showed an earlier onset of action (Kaplan-Meier analysis; log-rank test P<.006) beginning in the first week. The plasma concentrations of corticotropin and deoxycortisol were significantly higher during metyrapone treatment (multivariate analysis of covariance, P<.05), whereas cortisol remained largely unchanged. Metyrapone treatment was well tolerated without serious adverse effects. CONCLUSIONS: Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.     

Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial

BACKGROUND: High-frequency left-sided repetitive transcranial magnetic stimulation (HFL-TMS) has been shown to have antidepressant effects in double-blind trials. Low-frequency stimulation to the right prefrontal cortex (LFR-TMS) has also shown promise, although it has not been assessed in treatment-resistant depression and its effects have not been compared with those of HFL-TMS. OBJECTIVE: To prospectively evaluate the efficacy of HFL-TMS and LFR-TMS in treatment-resistant depression and compared with a sham-treated control group. DESIGN: A double-blind, randomized, sham-controlled trial. SETTING: Two general psychiatric services. PARTICIPANTS: Sixty patients with treatment-resistant depression who had failed to respond to therapy with multiple antidepressant medications were divided into 3 groups of 20 that did not differ in age, sex, or any clinical variables. All patients completed the double-blind phase of the study. INTERVENTIONS: Twenty 5-second HFL-TMS trains at 10 Hz and five 60-second LFR-TMS trains at 1 Hz were applied daily. Sham stimulation was applied with the coil angled at 45 degrees from the scalp, resting on the side of one wing of the coil.Main Outcome Measure Score on the Montgomery-Asberg Depression Rating Scale. RESULTS: There was a significant difference in response among the 3 groups (F56,2 = 6.2), with a significant difference between the HFL-TMS and sham groups and between the LFR-TMS and sham groups (P<.005 for all) but not between the 2 treatment groups. Baseline psychomotor agitation predicted successful response to treatment. CONCLUSIONS: Both HFL-TMS and LFR-TMS have treatment efficacy in patients with medication-resistant major depression. Treatment for at least 4 weeks is necessary for clinically meaningful benefits to be achieved. Treatment with LFR-TMS may prove to be an appropriate initial repetitive TMS strategy in depression taking into account safety, tolerability, and efficacy considerations.     

Randomized, placebo-controlled trial of nefazodone maintenance treatment in preventing recurrence in chronic depression.

BACKGROUND: Maintenance treatment to prevent recurrences is recommended for chronic forms of major depressive disorder (MDD), but few studies have examined maintenance efficacy of antidepressants with chronic MDD. This randomized, placebo-controlled study of the efficacy and safety of nefazodone in preventing recurrence was conducted for patients with chronic MDD. METHODS: A total of 165 outpatients with chronic, nonpsychotic MDD, MDD plus dysthymic disorder ("double-depression"), or recurrent MDD with incomplete inter-episode recovery, who achieved and maintained a clinical response during acute and continuation treatment with either nefazodone alone or nefazodone combined with psychotherapy, were randomized to 52 weeks of double-blind nefazodone (maximum dose 600 mg/day) or placebo. The occurrence of major depressive episodes during maintenance treatment was assessed with the 24-item Hamilton Rating Scale for Depression, a DSM-IV MDD checklist, and a blinded review of symptom exacerbations by a consensus committee of research clinicians. RESULTS: Application of a competing-risk model that estimated the conditional probability of recurrence among those patients remaining on active therapy revealed a significant (p =.043) difference between nefazodone (n = 76) and placebo (n = 74) when the latter part of the 1-year maintenance period was emphasized. At the end of 1 year, the conditional probability of recurrence was 30.3% for nefazodone-treated patients, compared with 47.5% for placebo-treated patients. Prior concomitant psychotherapy during acute/continuation treatment, although enhancing the initial response, was not associated with lower recurrence rates. Discontinuations due to adverse events were relatively low for both nefazodone (5.3%) and placebo (4.8%). Somnolence was significantly greater among the patients taking active medication (15.4%), compared with placebo (4.6%). CONCLUSIONS: Nefazodone is well-tolerated and is an effective maintenance therapy for chronic forms of MDD.     

Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial

OBJECTIVE: Epidemiological, biological marker and treatment studies, as well as neuroscientific theories, indicate a possible link between omega-3 fatty acids and perinatal depression (PND). Hence the aim of the present study was to assess whether omega-3 fatty acid treatment is superior to placebo in the treatment of PND. METHOD: A double-blind randomized placebo-controlled trial was undertaken. Women with major depression during the perinatal period received either fish oil or placebo for six weeks. Changes in depression scores were recorded weekly. RESULTS: A total of 26 subjects were recruited and there was no significant difference in depression scores between those receiving fish oil and those receiving the placebo. CONCLUSIONS: This is formally a negative study, suggesting that there is no benefit for omega-3 fatty acids over placebo in treating PND. The reason could be that the study was underpowered due to recruitment difficulties and therefore we suggest that it may be unwise to interpret this result as conclusive. Omega-3 is a natural product that is a safe and well-tolerated treatment. Further research is therefore needed in this area to establish whether omega-3 fatty acids are an effective treatment for PND.     

Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled,randomized clinical trial

BACKGROUND: This report presents results from the acute treatment phase of a clinical trial designed to confirm efficacy of a fixed dose of 20 mg of fluoxetine in children and adolescents with major depressive disorder (MDD). METHOD: After a 3-week screening period, 122 children and 97 adolescents with MDD ( ) were randomly assigned to placebo or fluoxetine. After a 1-week placebo lead-in, fluoxetine-treated patients received fluoxetine 10 mg/day for 1 week, then fluoxetine 20 mg/day for 8 weeks. RESULTS: Fluoxetine was associated with greater mean improvement in Children's Depression Rating Scale-Revised (CDRS-R) score than placebo after 1 week ( <.05) and throughout the study period. Significantly more fluoxetine-treated patients (41%) met the prospectively defined criteria for remission than did placebo-treated patients (20%) ( <.01). More fluoxetine- (65%) than placebo-treated (53%) patients met the prospectively defined response criterion of > or =30% decrease in CDRS-R score, but this difference was not significant ( =.093). Significantly more fluoxetine-than placebo-treated patients completed acute treatment ( =.001). There were no significant differences between treatment groups in discontinuations due to adverse events ( =.408). CONCLUSION: Fluoxetine 20 mg daily appears to be well tolerated and effective for acute treatment of MDD in child and adolescent outpatients. Fluoxetine is the only antidepressant that has demonstrated efficacy in two placebo-controlled, randomized clinical trials of pediatric depression.     

Fish oil supplementation in the treatment of major depression: a randomised double-blind placebo-controlled trial

Dietary deficiencies in essential omega-3 polyunsaturated fatty acids derived from fish are associated with depression and some fish oils may have therapeutic benefits. We aimed to determine whether taking tuna fish oil confers any additional benefit to conventional outpatient treatment for major depression. A randomized double-blind placebo-controlled four-month trial comparing tuna fish oil versus placebo was conducted on 83 outpatients with major depression. Despite large reductions in depression there were no significant differences at any assessment time point between patients receiving fish oil compared to placebo. Red blood cell incorporation of fatty acids indicated good compliance with oil supplementation, although this sample was not initially deficient in omega-3s. This particular dose and type of fish oil conferred no additional benefit to conventional treatment of depression in this sample. Future studies could target participants with pre-existing omega-3 deficiency and appraise alternate enriched types and higher doses of omega-3 supplementation.     

The use of pindolol with fluoxetine in the treatment of major depression: final results from a double-blind, placebo-controlled trial.

BACKGROUND: Preliminary reports have suggested that concomitant institution of pindolol and serotonin reuptake inhibitors robustly hastens clinical response; however, contradictory evidence from a randomized double-blind, controlled trial was recently reported by this group in a population of depressed patients who were prescribed fluoxetine and pindolol. Herein, we report final results from an extended sample size. METHODS: Drug-free outpatients with a major depressive episode were randomized in a double-blind manner to one of two treatment conditions: fluoxetine (20 mg daily) with pindolol (7.5 to 10 mg daily) or fluoxetine (20 mg daily) with placebo. After 6 weeks, patients were followed for 3 more weeks in a single-blind manner, on fluoxetine and placebo pindolol. RESULTS: Eighty-six patients completed at least 1 or more weeks on protocol, with 45 and 41 patients randomized to the pindolol and placebo groups respectively. After 2 weeks on protocol, partial remission (i.e., at least 50% decrease in depression rating scores from baseline) rates for pindolol (16%) and placebo (19%) groups were comparable. By the study's end, a partial remission was achieved, at least transiently, for 67% of the pindolol group and 80% of the placebo group. Pindolol treatment was associated with statistically significant reduction in blood pressure and pulse as compared to the control group. The two groups did not have overall differences in rates of attrition, time to response, and side effects. CONCLUSIONS: In accord with our previously published findings, these extended results do not support the efficacy of pindolol in hastening clinical response to fluoxetine in a patient population with predominantly chronic and recurrent depression.     

A randomized placebo-controlled trial of a school-based depression prevention program

OBJECTIVE: To conduct a placebo-controlled study of the effectiveness of a universal school-based depression prevention program. METHOD: Three hundred ninety-two students age 13 to 15 from two schools were randomized to intervention (RAP-Kiwi) and placebo programs run by teachers. RAP-Kiwi was an 11-session manual-based program derived from cognitive-behavioral therapy. The placebo was similar but with cognitive components removed. Outcomes were self-rated depression scales, the Reynolds Adolescent Depression Scale (RADS), and the Beck Depression Inventory II (BDI-II). Follow-up was to 18 months. Analysis was done on an intent-to-treat basis. RESULTS: Immediately after the intervention, depression scores were reduced significantly more by RAP-Kiwi than by placebo, with a mean difference in change from baseline between groups of 1.5 on BDI-II (CI > 0.38, p =.01) and 2.24 on RADS (CI > 0.22, p =.04). Categorical analysis confirmed significant clinical benefit with an absolute risk reduction of 3% (95% CI, 1-11%, McNemar chi, p =.03), with the "number needed to treat" for short-term benefit of 33. Group differences in depression scores averaged across time to 18 months were significant on RADS but not on BDI-II. Retention rates were 91% at 6 months and 72% at 18 months. CONCLUSIONS: The RAP-Kiwi program is a potentially effective public health measure. Confirmation of effectiveness measuring episodes of depressive illness and broader measures of adjustment is warranted.     

Mortality and poststroke depression: a placebo-controlled trial of antidepressants

OBJECTIVE: Poststroke depression has been shown to increase mortality for more than 5 years after the stroke. The authors assessed whether antidepressant treatment would reduce poststroke mortality over 9 years of follow-up. METHOD: A total of 104 patients were randomly assigned to receive a 12-week double-blind course of nortriptyline, fluoxetine, or placebo early in the recovery period after a stroke. Mortality data were obtained for all 104 patients 9 years after initiation of the study. Demographic and clinical measurements were collected at 3, 6, 9, 12, 18, and 24 months after the stroke. Survival data were analyzed by using the Kaplan-Meier method. RESULTS: Of the 104 patients, 50 (48.1%) had died by the time of the 9-year follow-up. Of 53 patients who were given full-dose antidepressants, 36 (67.9%) were alive at follow-up, compared with only 10 (35.7%) of 28 placebo-treated patients, a significant difference. Logistic regression analysis showed that the beneficial effect of antidepressants remained significant both in patients who were depressed and in those who were nondepressed at enrollment, after the effects of other factors associated with mortality (i.e., age, coexisting diabetes mellitus, and chronic relapsing depression) were controlled. There were no intergroup differences in severity of stroke, impairment in cognitive functioning and activities of daily living impairment, and other medications received. CONCLUSIONS: Treatment with fluoxetine or nortriptyline for 12 weeks during the first 6 months poststroke significantly increased the survival of both depressed and nondepressed patients. This finding suggests that the pathophysiological processes determining the increased mortality risk associated with poststroke depression last longer than the depression itself and can be modified by antidepressants.     

Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial

Objective

This phase 3, randomized, double-blind, placebo-controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression.

Methods

Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale-Bipolar Version-Severity Scale (CGI-BP-S) depression subscore. Safety assessments included adverse events, laboratory evaluations, vital signs, extrapyramidal symptoms (EPS), and suicidality.

Results

Patients treated with adjunctive lumateperone 42 mg showed significantly greater improvement compared with adjunctive placebo in MADRS Total score (LS mean difference vs placebo [LSMD], −2.4; p = 0.02) and CGI-BP-S depression subscore (LSMD, −0.3; p = 0.01), while adjunctive lumateperone 28 mg showed numerical improvement in MADRS Total score (LSMD, −1.7; p = 0.10) and improvement in the CGI-BP-S depression subscore (LSMD, −0.3; p = 0.04). Adjunctive lumateperone treatment was well tolerated; treatment-emergent adverse events reported at rates >5% and twice placebo for lumateperone 42 mg were somnolence (11.3%), dizziness (10.7%), and nausea (8.5%), with minimal risk of EPS, metabolic abnormalities, or increased prolactin.

Conclusions

Lumateperone 42-mg treatment adjunctive to lithium or valproate significantly improved depression symptoms and was generally well tolerated in patients with MDEs associated with either bipolar I or bipolar II disorder.     

Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial

OBJECTIVE: This study determined the efficacy of antidepressant medication for the treatment of depression in the "old-old." METHOD: This randomized 8-week medication trial compared citalopram, 10-40 mg/day, to placebo in the treatment of patients 75 and older with unipolar depression. RESULTS: A total of 174 patients who were 58% women with a mean age of 79.6 years (SD=4.4) and a mean baseline Hamilton Depression Rating Scale score of 24.3 (SD=4.1) were randomly assigned to treatment at 15 sites. There was a main effect for site but not for treatment condition. The remission rate, defined as a final Hamilton depression scale score <10, was 35% for the citalopram and 33% for the placebo groups. However, patients with severe depression (baseline Hamilton depression scale score >24) tended to have a higher remission rate with medication than with placebo (35% versus 19%). CONCLUSIONS: In the oldest group of community-dwelling patients to be studied to date, medication was not more effective than placebo for the treatment of depression. However, given the considerable psychosocial support received by all patients, the placebo condition represents more than the ingestion of an inactive pill. Across sites, there was considerable range in response to medication, 18% to 82%, and to placebo, 16% to 80%.     

Sarizotan as a treatment for dyskinesias in Parkinson's disease: a double-blind placebo-controlled trial.

The objective of this study is to conduct a dose-finding study of sarizotan in Parkinson's disease (PD) patients with dyskinesia to identify a safe dose and to identify a sensitive dyskinesia rating measure. Sarizotan is a novel compound with full 5-HT(1A) agonist properties and additional high affinity for D(3) and D(4) receptors. An open label study documented improvements in PD patients with levodopa-induced dyskinesia. There is no precedent for study designs or outcome measures in pivotal trials of antidyskinesia therapies. The approach used here was a multicenter, randomized, placebo-controlled, double-blind, parallel study. Included were PD patients optimized to levodopa and dopaminergic drugs with moderately disabling dyskinesias present greater than or equal to 25% of the waking day. Interventions included sarizotan 2, 4, or 10 mg/day or matching placebo, given in two doses. There were two outcome measures: the primary measure was change from baseline in diary-based on time without dyskinesia; the secondary measures were change from baseline in scores on the Abnormal Involuntary Movement Scale (AIMS), the composite score of Unified Parkinson's Disease Rating Scale (UPDRS) Items 32+33 (dyskinesia duration and disability) and total UPDRS. A total of 398 subjects were randomized, with 381 included in the intention-to-treat population. No significant changes occurred on sarizotan compared to placebo on any diary-based measure of dyskinesia or the AIMS score. The composite score of UPDRS Items 32+33 was significantly improved with 2 mg/day sarizotan, with a trend at 10 mg/day. Adverse events were not significantly different in sarizotan- and placebo-treated patients, but off time significantly increased with sarizotan 10 mg/day. Sarizotan 2 mg/day is a safe agent in PD patients with dyskinesia. To test its role in abating dyskinesia, future studies should focus on this dose and will use the composite score of UPDRS Items 32+33 as the primary outcome.     

A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents

OBJECTIVE: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression. METHOD: An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children (ages 7-11) and adolescents (ages 12-17) with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients (N=174) were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children's Depression Rating Scale-Revised; the response criterion was defined as a score of < or =28. RESULTS: The overall mean citalopram dose was approximately 24 mg/day. Mean Children's Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study (effect size=2.9). The difference in response rate at week 8 between placebo (24%) and citalopram (36%) also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups (5.9% versus 5.6%, respectively). Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group. CONCLUSIONS: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.     

Moclobemide and clomipramine in reactive depression. A placebo-controlled randomized clinical trial

The purpose of this study was to compare moclobemide and clomipramine in reactive depression according to the Newcastle II classification. Sixty patients were allocated to either 300 mg moclobemide, 150 mg clomipramine or placebo, all divided in 3 daily doses. Improvements occurred over time, but differences between treatments and compared with placebo were never statistically significant. Dizziness, tremor and anticholinergic symptoms were significantly more frequent with clomipramine than with moclobemide and placebo.     

Psychosis after epilepsy surgery: Report of three cases

Temporal lobe epilepsy surgery has become a successful alternative in patients with refractory epilepsy. However, the outcome of epilepsy surgery may be affected by the occurrence of postsurgical psychiatric symptoms, such as psychosis. This report describes three cases of refractory temporal lobe epilepsy and hippocampal sclerosis, which, after anterior temporal lobectomy, presented with acute psychosis. One of them had a history of acute psychosis, and all of them met criteria for Cluster A personality disorder (schizoid/schizotypal) during psychiatric assessment prior to surgery. The three cases had a good seizure outcome (Engel I), but, on follow-up during the first year after surgery, developed an acute psychotic episode compatible with schizoaffective disorder; brief psychotic disorder; and a delusional disorder, respectively, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Treatment with low-dose risperidone was successful.     

Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial

Methylation has been implicated in the etiology of psychiatric illness. Parenteral S-adenosylmethionine, a methyl group donor, has been shown to be an effective antidepressant. The authors studied the antidepressant effect of oral S-adenosylmethionine in a randomized, double-blind, placebo-controlled trial for 15 inpatients with major depression. The results suggest that oral S-adenosylmethionine is a safe, effective antidepressant with few side effects and a rapid onset of action. S-Adenosylmethionine induced mania in a patient with no history of mania. S-Adenosylmethionine may be useful for patients who cannot tolerate tricyclic anti-depressants. These findings support a role for methylation in the pathophysiology of depression.     

Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial

BACKGROUND: Antidepressant treatments that achieve a higher remission rate than those currently available are urgently needed. The thyroid hormone triiodothyronine may potentiate antidepressant effects. OBJECTIVE: To determine the antidepressant efficacy and safety of liothyronine sodium (triiodothyronine) when administered concurrently with the selective serotonin reuptake inhibitor sertraline hydrochloride to patients with major depressive disorder. DESIGN: Double-blind, randomized, 8-week, placebo-controlled trial. SETTING: Outpatient referral centers. PATIENTS: A total of 124 adult outpatients meeting unmodified DSM-IV criteria for major depressive disorder without psychotic features. INTERVENTIONS: Patients were randomized to receive sertraline hydrochloride (50 mg/d for 1 week; 100 mg/d thereafter) plus liothyronine sodium (20-25 microg/d for 1 week; 40-50 microg/d thereafter) or sertraline plus placebo for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was categorical response to treatment (> or =50% decrease in scores on the 21-item Hamilton Rating Scale for Depression from baseline to study end point). Remission rate (final Hamilton Rating Scale for Depression score, < or =6) was a secondary outcome measure. RESULTS: Intent-to-treat Hamilton Rating Scale for Depression response rates were 70% and 50% in the sertraline-liothyronine and sertraline-placebo groups, respectively (P = .02; odds ratio, 2.93; 95% confidence interval, 1.23-7.35); remission rates were 58% with sertraline-liothyronine and 38% with sertraline-placebo (P = .02; odds ratio, 2.69; 95% confidence interval, 1.16-6.49). Baseline T(3) values were lower in patients treated with sertraline-liothyronine who had remissions than in those without remissions (t(48) = 3.36; P<.002). Among patients treated with sertraline-liothyronine, remission was associated with a significant decrease in serum thyrotropin values (F(1,73) = 4.00; P<.05). There were no significant effects of liothyronine supplementation on frequency of adverse effects. CONCLUSIONS: These results demonstrate enhancement of the antidepressant effect of sertraline by concurrent treatment with liothyronine without a significant increase in adverse effects. The antidepressant effect of liothyronine may be directly linked to thyroid function.