Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression.

Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.

ABCB1 (MDR1) predicts remission on P-gp substrates in chronic depression.

The hypothesis that allelic variation in the multidrug resistance-1 (MDR1 or ABCB1) gene encoding the P-glycoprotein (P-gp) blood-brain barrier efflux pump is associated with remission and side effects was tested in chronic major depression patients treated with P-gp substrates. In 83 patients from the REVAMP trial, frequency of and time to remission as well as side effects was tested among genotype groups at 6 ABCB1 single nucleotide polymorphisms (SNPs). These six SNPs are significantly associated with remission and time to remission, with minor allele carriers on rs2235040 and rs9282564 attaining statistical significance after controlling for the other ABCB1 SNPs. The six ABCB1 SNPs are also significantly associated with the average side effects. However, here common homozygotes on rs2235040 and rs9282564 demonstrated significantly higher side effects after controlling for the effects of the other ABCB1 SNPs. These findings confirm and extend previous observations that minor alleles of two ABCB1 SNPs predict remission to treatment with substrates and demonstrate that common homozygotes on these SNPs experience greater side effects. Results point to the potential importance of ABCB1 variation for personalized medicine approaches to treating depression.

Seizure duration with remifentanil/methohexital vs. methohexital alone in middle-aged patients undergoing electroconvulsive therapy.

BACKGROUND: The object of this study was to test whether substituting part of the methohexital dose with the short-acting opioid remifentanil would prolong seizure duration in middle-aged patients while providing a similar depth of anesthesia as with methohexital alone. This has been reported for the combined use of methohexital and remifentanil in elderly patients, but has not been investigated in middle-aged patients likely to require a higher total dose of methohexital for inducing anesthesia. METHOD: Seven patients (42+/-10 years; mean +/-SD) receiving electroconvulsive therapy (ECT) were anesthetized with methohexital (1.25 mg kg-1) or with methohexital (0.625 mg kg-1) plus remifentanil (1 micro g kg-1) in this randomized, double blind, crossover study. Additional methohexital was given as needed until loss of eyelash reflex was observed. Suxamethonium (1 mg kg-1) was used for muscular paralysis. RESULTS: Motor and EEG seizure durations were significantly longer after induction with methohexital plus remifentanil (45+/-14 and 58+/-15 s) than with methohexital alone (31+/-11 and 42+/-18 s). A methohexital dose of 1.2+/-0.3 and 1.9+/-0.3 mg was necessary to achieve loss of eyelash reflex if methohexital was used with and without remifentanil. Peak heart rate after ECT was significantly higher if remifentanil was coadministered with methohexital (148+/-12 vs. 126+/-24 b.p.m). CONCLUSION: Substituting part of the methohexital dose with remifentanil is a useful anesthetic technique to prolong seizure duration in middle-aged patients requiring a 1.5-fold higher induction dose of methohexital than elderly patients, the only population studied to date for the combined use of methohexital and remifentanil in ECT.

Fetal heart rate decelerations during ECT-induced seizures: is it important?

Electroconvulsive therapy (ECT) is sometimes indicated during pregnancy and may offer advantages over pharmacotherapy for the patient and the fetus (1,2). However, very little data is available on the impact of epileptic or ECT-induced seizures on the fetus. We report a case of brief fetal heart rate decelerations in a fetus associated with maternal ECT-induced convulsions.

Cortisol feedback during the HPA quiescent period in patients with major depression.

OBJECTIVE: The authors tested the hypothesis that patients with major depression have a defect in the mechanism by which cortisol exerts negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis during the HPA axis quiescent period. METHOD: Twenty-nine patients with major depression and 25 healthy comparison subjects were randomly assigned to administration of 15 mg cortisol or placebo infused over 2 hours beginning at 7:00 p.m. Cortisol and ACTH levels were measured at baseline and every 30 minutes from 7:30 p.m. to 11:00 p.m. RESULTS: Differences between the patients and the comparison subjects in the ACTH response to the cortisol infusion, relative to the ACTH response to placebo, were not found. CONCLUSIONS: The results provide some evidence that patients with major depression do not have an abnormality of cortisol feedback during the HPA axis quiescent period.

Sertraline versus imipramine to prevent relapse in chronic depression.

BACKGROUND: Chronic depressions are common, disabling and under-treated, and long-term treatment is little studied. We report the continuation phase results from a long-term treatment study. METHODS: After 12 weeks of acute phase treatment in a double-blind, randomized, parallel-group, multi-center trial of sertraline or imipramine, patients with chronic depression (> or = 2 years in major depression, or major depression superimposed on dysthymia) continued study drug for 16 weeks. Initially, 635 patients were randomized to sertraline or imipramine in a 2:1 ratio. Nonresponders after 12 weeks entered a 12-week double-blind crossover trial of the alternate medication. Entry into continuation treatment required at least a satisfactory response (partial remission) to initial or crossover treatment. RESULTS: Of 239 acute or crossover responders to sertraline, 60% entered continuation in full remission and 40% with a partial remission. These proportions were identical for imipramine patients (n = 147). For both drug groups, over two-thirds of those entering in full remission retained it. For those entering in partial remission, over 40% achieved full remission. Patients requiring crossover treatment were less likely to maintain or improve their response during continuation treatment. The two drugs did not differ significantly in response distribution, drop out rates or discontinuation due to side effects during continuation treatment. LIMITATIONS: The absence of a placebo group constrains interpretation of our results, but chronic depressions have low placebo response rates. CONCLUSIONS: Most chronic depression patients who remit with 12 weeks of sertraline or imipramine treatment maintain remission during 16 weeks of continuation treatment. Most patients with a satisfactory therapeutic response (partial remission) after 12 weeks of treatment maintain it or further improve. Patients treated with imipramine experienced more side effects, but both drugs were well tolerated.

Is electroconvulsive therapy effective for the depressed patient with comorbid borderline personality disorder?

Among the more common current indications for electroconvulsive therapy (ECT) is treatment-resistant depression. Treatment resistance is correlated with a number of factors, including the presence of comorbid personality disorders, such as borderline personality disorder (BPD). A detailed review of the literature was undertaken and very few reports or studies have dealt specifically with ECT in borderline patients. Thirteen original reports on ECT outcome in personality disordered patients were identified. Depressed patients with a personality disorder, particularly BPD, may have a poorer outcome on some measures. However, the available data suggests that depression in these patients can be effectively treated with ECT. The depressed, borderline patient appears to have two distinct disorders, one which is responsive to ECT and the other which is not. Unfortunately, the literature is limited by lack of rigorous randomized treatment studies, lack of long-term follow-up, and other methodological weaknesses. Clinical guidelines are suggested.

Psychopharmacologic treatment strategies for depression, bipolar disorder, and schizophrenia.

Patients with serious psychiatric disorders are frequently treated by primary care physicians, who may have difficulty keeping up with recent advances in psychiatry. This paper presents an updated synopsis for three major psychiatric illnesses: major depression, bipolar disorder, and schizophrenia. Current definitions, updated diagnostic criteria, short- and long-term treatment strategies with algorithms, and special challenges for the clinician are discussed for each of these illnesses. On the basis of each illness's distinct characteristics, five treatment principles are emphasized: 1) Treatment strategies should be long-term and should emphasize adherence, 2) treatment choice should be empirical, 3) combinations of medications may be helpful, 4) a combination of psychosocial and pharmacologic treatments may be more useful than either alone, and 5) the family or "significant others" as well as a consumer organization need to be involved. Some of the new directions in dinical research to refine these strategies and meet these challenges are also described.

24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression.

BACKGROUND: Considerable research has been devoted to the hypothalamic-pituitary-adrenal (HPA) axis in depression, but relatively little attention has been given to intensive monitoring of hormone secretion over time. Such research is potentially important because the HPA axis has prominent circadian and ultradian periodicity. Comparison of depressed patients with and without psychotic features is also important because HPA axis abnormalities may be especially pronounced in psychotic depressed patients. METHODS: Eleven patients with psychotic major depression (PMD patients), 38 patients with nonpsychotic major depression (NPMD patients), and 33 healthy control subjects, all drug free, were studied. Patients with PMD and NPMD were outpatients recruited primarily by advertisement. Subjects were admitted to a General Clinical Research Center and had blood drawn through an intravenous line for determination of cortisol and corticotropin (ACTH) levels every hour for 24 hours. RESULTS: Among NPMD patients, the 24-hour cortisol amplitude was significantly (P =.02) reduced in comparison with control subjects, while ACTH indices did not differ between NPMD patients and the control group. Among PMD patients, the ACTH 24-hour mean was significantly (P =.03) increased compared with controls, while PMD patients and the control group did not differ significantly in cortisol indices. CONCLUSION: In the population studied, PMD and NPMD patients have distinct profiles of HPA axis dysregulation.

Acute antidepressant effects of intravenous hydrocortisone and CRH in depressed patients: a double-blind, placebo-controlled study.

OBJECTIVE: The primary objective of this investigation was to examine the acute antidepressant effects of intravenous hydrocortisone and ovine corticotropin releasing hormone (CRH) infusions in patients with major depression. METHOD: Twenty-two patients who met DSM-III-R criteria for nonpsychotic major depression were randomly assigned to receive intravenously 1 mg/kg of ovine CRH, 15 mg of hydrocortisone, or saline under double-blind conditions on day 1. Standard depression rating scales were completed on day 1 before the study medications were administered and again the following day (day 2). RESULTS: Patients treated with hydrocortisone demonstrated a significantly greater reduction in total 21-item Hamilton Depression Rating Scale scores (mean reduction=8.4 points or 37%) than patients given ovine CRH (mean=1.2 points) or placebo (mean=1.3 points). CONCLUSIONS: Acute hydrocortisone infusion is associated with a rapid and robust reduction in depressive symptoms. The authors discuss the therapeutic implications of these findings.

Neuropsychological deficits in psychotic versus nonpsychotic major depression and no mental illness.

OBJECTIVE: At least three studies have indicated that patients with psychotic major depression studied under non-drug-free conditions differ from patients with nonpsychotic major depression and healthy comparison subjects on several measures of neuropsychological performance. The current study explored specific impairments in cognitive function in subjects with psychotic major depression, subjects with nonpsychotic major depression, and healthy comparison subjects studied under drug-free conditions. METHOD: A battery of neuropsychological tests was administered to 11 patients with psychotic major depression, 32 patients with nonpsychotic major depression, and 23 normal comparison subjects under drug-free conditions. The three groups did not differ statistically in age, sex, or level of education. To ensure that participants had minimal levels of severity and endogenicity, all patients were required to have a score of at least 20 on the 21-item Hamilton Depression Rating Scale and a score of at least 7 on the Core Endogenomorphic Scale, which uses eight items from the Hamilton depression scale. RESULTS: Patients with psychotic major depression demonstrated significantly greater impairment than patients with nonpsychotic major depression and/or comparison subjects in attention and response inhibition (as measured by the Stroop color-word subscale score) as well as in verbal declarative memory (as measured by the Paragraph Recall Test). CONCLUSIONS: These data indicate that patients with psychotic major depression demonstrate impairment in functions thought to be mediated by the frontal cortex and mediotemporal lobes.

Phenomenology and treatment of agitation.

Agitation is a troublesome, common symptom in major depression that can be difficult to manage. It is sometimes a side effect of antidepressant treatment and may occasionally represent a mixed bipolar episode. If agitation fails to respond to an antidepressant alone, treatment may be augmented with a benzodiazepine, a neuroleptic, or lithium. Preliminary evidence indicates that divalproex, which has been found useful for bipolar disorder and for agitation associated with Alzheimer's disease, may also be effective for agitated depression. A controlled trial is now underway.

The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder.

BACKGROUND: This article describes the development of consensus medication algorithms for the treatment of patients with major depressive disorder in the Texas public mental health system. To the best of our knowledge, the Texas Medication Algorithm Project (TMAP) is the first attempt to develop and prospectively evaluate consensus-based medication algorithms for the treatment of individuals with severe and persistent mental illnesses. The goals of the algorithm project are to increase the consistency of appropriate treatment of major depressive disorder and to improve clinical outcomes of patients with the disorder. METHOD: A consensus conference composed of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of major depressive disorder in the Texas mental health system. After a series of presentations and panel discussions, the consensus panel met and drafted the algorithms. RESULTS: The panel consensually agreed on algorithms developed for both nonpsychotic and psychotic depression. The algorithms consist of systematic strategies to define appropriate treatment interventions and tactics to assure optimal implementation of the strategies. Subsequent to the consensus process, the algorithms were further modified and expanded iteratively to facilitate implementation on a local basis. CONCLUSION: These algorithms serve as the initial foundation for the development and implementation of medication treatment algorithms for patients treated in public mental health systems. Specific issues related to adaptation, implementation, feasibility testing, and evaluation of outcomes with the pharmacotherapeutic algorithms will be described in future articles.

Serotonergic synergism: the risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs.

It has become common clinical practice to combine the selective serotonin reuptake inhibitors with other serotonergic agents for augmentation or adjunctive purposes. The empirical basis for using these combinations remains limited, but is growing. Also growing is a literature that suggests that even the most apparently benign combinations of serotonergic drugs carry at least some risk of serious pharmacokinetic or pharmacodynamic drug interactions, such as a serotonin syndrome.

ECT in dissociative identity disorder and comorbid depression.

Dissociative identity disorder (DID), previously named multiple personality disorder, is a diagnosis often complicated by comorbid major depression. We report on four cases of DID associated with severe self-destructive behavior and comorbid major depression treated with electroconvulsive therapy (ECT). In three of the patients, ECT appeared to be helpful in treating the comorbid depression without adversely affecting the DID. The potential risks of using ECT in patients with DID are reviewed.