Adequate Antidepressant Trials Research Articles

Deep Brain Stimulation for Treatment-Resistant Depression

Brian did reasonably well for about 3 years, with occasional worsening of depressive symptoms but generally with good functioning, when he developed his current major depressive episode. This was his most severe episode to date, with active suicidal ideation with a plan (but no immediate intent) to shoot himself. Over the next year, he had a number of treatments, among them multiple antidepressant medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, mirtazapine, tricyclic antidepressants, and tranylcypromine, as well as augmentation with lithium, thyroid hormone, buspirone, atypical antipsychotics, anticonvulsants, stimulants, light therapy, and ongoing psychotherapy. No treatment was able to achieve remission or a persistent clinically signifi cant reduction in symptoms. Given his degree of treatment resistance and continued overall deterioration, including increased suicidal ideation, he was referred for ECT. He achieved a good response (50%‐60% symptom reduction) with eight highdose right unilateral ECT treatments. ECT was delivered concurrently with ongoing medications, and attempts were made to optimize medications during and after ECT. However, Brian relapsed in about 6 weeks, and repeat ECT (including four right unilateral and eight bitemporal treatments delivered concurrently with ongoing medications) was unsuccessful in achieving signifi cant symptom reduction but was associated with notable cognitive impairment.

The NeuroStar TMS Device: Conducting the FDA Approved Protocol for Treatment of Depression

The Neuronetics NeuroStar Transcranial Magnetic Stimulation (TMS) System is a class II medical device that produces brief duration, pulsed magnetic fields. These rapidly alternating fields induce electrical currents within localized, targeted regions of the cortex which are associated with various physiological and functional brain changes. In 2007, O'Reardon et al., utilizing the NeuroStar device, published the results of an industry-sponsored, multisite, randomized, sham-stimulation controlled clinical trial in which 301 patients with major depression, who had previously failed to respond to at least one adequate antidepressant treatment trial, underwent either active or sham TMS over the left dorsolateral prefrontal cortex (DLPFC). The patients, who were medication-free at the time of the study, received TMS five times per week over 4-6 weeks. The results demonstrated that a sub-population of patients (those who were relatively less resistant to medication, having failed not more than two good pharmacologic trials) showed a statistically significant improvement on the Montgomery-Asberg Depression Scale (MADRS), the Hamilton Depression Rating Scale (HAMD), and various other outcome measures. In October 2008, supported by these and other similar results, Neuronetics obtained the first and only Food and Drug Administration (FDA) approval for the clinical treatment of a specific form of medication-refractory depression using a TMS Therapy device (FDA approval K061053). In this paper, we will explore the specified FDA approved NeuroStar depression treatment protocol (to be administered only under prescription and by a licensed medical profession in either an in- or outpatient setting).

The NeuroStar TMS Device: Conducting the FDA Approved Protocol for Treatment of Depression

The Neuronetics NeuroStar Transcranial Magnetic Stimulation (TMS) System is a class II medical device that produces brief duration, pulsed magnetic fields. These rapidly alternating fields induce electrical currents within localized, targeted regions of the cortex which are associated with various physiological and functional brain changes.1,2,3 In 2007, O'Reardon et al., utilizing the NeuroStar device, published the results of an industry-sponsored, multisite, randomized, sham-stimulation controlled clinical trial in which 301 patients with major depression, who had previously failed to respond to at least one adequate antidepressant treatment trial, underwent either active or sham TMS over the left dorsolateral prefrontal cortex (DLPFC). The patients, who were medication-free at the time of the study, received TMS five times per week over 4-6 weeks.4 The results demonstrated that a sub-population of patients (those who were relatively less resistant to medication, having failed not more than two good pharmacologic trials) showed a statistically significant improvement on the Montgomery-Asberg Depression Scale (MADRS), the Hamilton Depression Rating Scale (HAMD), and various other outcome measures. In October 2008, supported by these and other similar results5,6,7, Neuronetics obtained the first and only Food and Drug Administration (FDA) approval for the clinical treatment of a specific form of medication-refractory depression using a TMS Therapy device (FDA approval K061053). In this paper, we will explore the specified FDA approved NeuroStar depression treatment protocol (to be administered only under prescription and by a licensed medical profession in either an in- or outpatient setting).

RESEARCH: Validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ)

The low rate of response to antidepressants in treatment resistant depression (TRD) justifies studies of next-step therapies following a treatment failure. In TRD clinical trials, it is important to verify the accurate diagnosis of treatment resistance for all enrolled subjects using a reliable and valid instrument. Self-rated scales can reduce the impact of investigator bias and reduce the time burden for clinical researchers. The Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) is a self-rated scale used to determine treatment resistance in major depressive disorder (MDD). The ADAPT-A study is a multi-center double-blind, placebo-controlled study of low-dose aripiprazole adjunctive to ADT among outpatients with TRD. At the screening assessment, potential subjects completed the MGH ATRQ. The ADAPT-A medical monitors subsequently performed remote patient interviews and obtained detailed medication histories. The data obtained from the MGH ATRQ and by the medical monitors were compared for congruency. Of the 186 patients enrolled by the local sites, no subjects deemed treatment resistant by the MGH ATRQ were found to be nonresistant by the medical monitors. In 76.3% (n = 142) of the subjects, the number of failed adequate antidepressant trials reported by the MGH ATRQ was concordant with the data collected by medical monitors. In 16.1% (n = 30) of all cases, the medical monitors found a greater number of failed trials; in 7.5% (n = 14) of cases, the medical monitors found fewer failed medication trials. The discrepancy was by more than one medication trial in only 4.0% (n = 7) of cases. We found the MGH ATRQ to be relatively concordant in its assessment of treatment resistance in depression compared with independent clinical researchers. Although the MGH ATRQ tended to underreport the number of unsuccessful treatment trials relative to the clinical interviews, its accuracy in cases it detected was confirmed by raters.

Identification of clinical factors associated with resistance to antidepressants in bipolar depression: results from an European Multicentre Study

This study is the first investigation to identify clinical factors associated with treatment resistance in bipolar depression (TRBD). TRBD is defined as failure to respond to at least two consecutive adequate antidepressant trials. The primary objective of this European Multicenter Study was to identify specific clinical and demographic factors associated with TRBD in a sample of bipolar patients treated for a major depressive episode. A total of 261 bipolar patients with major depressive episode were included in the analysis. Among them, 162 patients were considered as responders to treatment and the remaining 99 patients were considered as treatment resistant with a 17-item Hamilton Rating Scale for Depression Score remaining superior or equal to 17 after two consecutive adequate antidepressant trials. Cox regression analysis was used to examine the association between individual clinical variables and TRBD. We found four clinical variables to be significantly associated with TRBD: melancholia [P=0.01, odds ratio (OR)=2.4], comorbidity with social phobia (P=0.02, OR=2.3), current suicidal risk (P=0.02, OR=1.8) and severe intensity of current depressive episode (P=0.01, OR=1.8). Our findings identify four clinical variables associated with TRBD, which could be further investigated in controlled prospective trials.

Identification of bipolar disorder in women with postpartum depression

No studies to date have assessed the pharmacological management of treatment-resistant postpartum depression. We reviewed the pharmacological treatment of postpartum depression in patients diagnosed with treatment-resistant 'unipolar' depression. We conducted a chart review of patients treated consecutively at a perinatal clinic. Treatment-resistant postpartum depression was defined as a failure to respond to at least one adequate antidepressant trial. Patients were diagnosed using the DSM-IV criteria, and the Clinical Global Impression-Improvement (CGI-I) rating scale was used to assess response to various pharmacological interventions. The majority of patients (57%, 34/60) referred for postpartum depression actually suffered from bipolar disorder. All patients were on antidepressants at the time of referral, but by the end of the study 37% (22/60) continued on antidepressants alone or in combination with other medications. CGI-I ratings showed appreciable improvement in depression at the end of six months following the initial consultation. Very much improvement was noted in 65% (39/60) of patients, and 22% (13/60) were considered much improved. The most common change in medication was a switch to or addition of an atypical neuroleptic. Retrospective design, small sample size, and lack of a control group. Management of treatment resistance in women with postpartum depression should be considered within the context of types of mood disorders. Atypical neuroleptics and mood stabilizers used alone or as adjuncts should be considered in the treatment of resistant postpartum depression in patients with a bipolar diathesis.

Suicidal Ideation Abates After Ketamine Infusion

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessSuicidal Ideation Abates After Ketamine InfusionJun YanJun YanSearch for more papers by this authorPublished Online:16 Oct 2009https://doi.org/10.1176/pn.44.20.0021Research conducted in the past few years shows that ketamine leads to a rapid antidepressant effect within hours of administration. A recent study has demonstrated how this mood change translates into a tangible protection against suicidal ideation in treatment-resistant patients with depression (see Original article: Ketamine Leaves BDNF Unchanged for more on ketamine treatment).Ketamine is an anesthetic given intravenously that is often used in surgery and in veterinary medicine. It is known to cause psychosis and has raised abuse concerns. In a paper published in the September 1 Biological Psychiatry, researchers at Mount Sinai School of Medicine, Rutgers University, and Harvard University conducted two clinical studies in which they assessed suicidal ideation in patients with treatment-resistant depression. The study was funded by the National Institutes of Health.Twenty-six patients participated in the first study, in which each received a single infusion of ketamine at a dose of 0.5 mg/kg and was then kept in the hospital for 28 hours. Outcomes were measured 24 hours after the infusion using the single suicide-related item in the Montgomery-Asberg Depression Rating Scale (MADRS-SI). Scores ranged from 0 to 6, with a score of 6 indicating “explicit plans for suicide when there is an opportunity” or “active preparations for suicide.”Subjects' mean score on the MADRS-SI scale decreased from 2.85 before the ketamine infusion to 0.77 at 24 hours after the infusion, which was statistically significant. Before the infusion, 13 patients had a score of 4 or above on the scale. Twenty-four hours after the infusion, eight of the 13 patients had a score of 0 or 1 and three had a score of 2 or 3; two remained at or above a score of 4.Ten of the 26 patients also completed the Implicit Association Test, a behavioral-assessment instrument the researchers used to measure the implicit suicidal intention before and after the infusion. The implicit and explicit suicidal association scores also decreased significantly after the ketamine infusion.Ten of the patients who had been deemed responders in the first study participated in the second study and received repeated ketamine infusions three times a week in a period of 12 days for up to six infusions. Their average MADRS-SI score was 3.0 at baseline. Nine patients scored 0 on the MADRS-SI scale after every repeated infusion. One patient had a score of 2 after the first infusion (baseline score 4). The patient was dropped from further infusion because of lack of response in overall depressive symptoms, defined as at least 50 percent reduction in MADRS total score.The effect of ketamine on suicidal ideation was likely an indirect result of the antidepressant effect of the drug, the authors concluded after they analyzed the correlation between the total score of the nonsuicide-related items in the MADRS and the suicide-related item score. The 26 patients in the single-dose study had an average preinfusion MADRS total score of 37 (scale range 0-60), which decreased to 15 at 24 hours after the infusion. Seventeen of these patients had a 50 percent reduction in MADRS total score.All study participants had moderate to severe depression as indicated by an Inventory of Depression Symptomatology score of 32 or above at baseline and had failed at least two adequate antidepressant trials in the current depressive episode. They had been suffering from major depressive disorder for a mean of 29 years. All had been in the current depressive episode for at least two years and failed an average of six antidepressants in the current episode. Five of the 26 participants had a history of suicide attempts.No patient experienced hallucinations during the studies, Rebecca Price, M.S., a Ph.D. candidate in psychology at Rutgers University and the lead author of the article, told Psychiatric News. The psychotomimetic side effects observed in the studies were “minimal” at this low dose of ketamine, she said, and additional results and analyses are pending publication.The rapid antidepressant effect of ketamine infusion has previously been reported in small clinical trials conducted by researchers at the Mood and Anxiety Disorders Program at the National Institute of Mental Health (NIMH). The NIMH researchers also demonstrated that ketamine's mechanism of action may lie in its antagonism of the NMDA (N-methyl d-aspartate) receptors and subsequent activation of the AMPA (amino-3-hydroxy-5 methylisoxazole-4-propionic acid) receptors; both are biologically activated by the neurotransmitter glutamate (Psychiatric News, September 7, 2007).An abstract of “Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression” is posted at<www.journals.elsevierhealth.com/periodicals/bps/article/S0006-3223(09)00519-8/abstract>.▪ ISSUES NewArchived

Is Baseline Medication Resistance Associated With Potential for Relapse After Successful Remission of a Depressive Episode With ECT?

To test whether pre-electroconvulsive therapy (ECT) medication resistance is associated with post-ECT relapse rates. In a post hoc analysis of data from a large multicenter trial of post-ECT relapse prevention strategies (conducted from May 1997 to July 2004), we assessed whether response to antidepressant medications prior to ECT for a unipolar nonpsychotic depressive episode (DSM-IV) was associated with differential relapse rates after remission with ECT. Baseline (i.e., pre-ECT) medication use was assessed with the Antidepressant Treatment History Form. Following remission with ECT that was stable for 1 week, patients were randomly assigned to receive 6 months of treatment with either combination lithium carbonate/nortriptyline or continuation ECT. Relapse was assessed with the 24-item Hamilton Rating Scale for Depression. There were 146 patients followed in the first week after remission (termed the interim week in this study), and 73 in the randomized phase of the study. For the purposes of this trial, medication resistance is defined as not having responded to at least 1 adequate trial of an antidepressant medication before ECT. In the first week after acute remission, 9.8% of patients not having at least 1 antidepressant medication trial met relapse criteria, while 31.4% of medication-resistant patients met relapse criteria, a difference that was statistically significant (p = .026). In the randomized phase of the study, 34.6% of non-medication-resistant patients relapsed, while 50.0% of medication-resistant patients relapsed, a difference that was not significant (p = .434). We conclude that nonpsychotic patients who had at least 1 adequate antidepressant medication trial before ECT may be especially prone to early relapse after successful acute remission with ECT.

Predictors of Major Depression Six Months After Admission for Outpatient Treatment

This study examined the rate and predictors of major depression six months after outpatient mental health admission. Assessments were conducted at admission and three and six months later among 166 participants. Antidepressant treatment adequacy and depression outcomes were assessed at follow-ups. Predictors of major depression at six months included nonremission status at three months (odds ratio [OR]=3.56, p=.003), inadequacy of early pharmacotherapy (OR=2.73, p=.009), worse physical functioning measured by the 36-Item Short-Form Health Survey (OR=.975, p<.001), and being unmarried (OR=2.54, p=.031). The findings support the effects of baseline physical disability, marital status, early treatment adequacy, and early remission on the course of major depression. The identification of individuals who do not receive intensive pharmacotherapy or who have not recovered by three months may provide opportunities for interventions to optimize six-month outcomes and to prevent the development of a persistent depression.

Chronic forms of major depression are still undertreated in the 21st century: Systematic assessment of 801 patients presenting for treatment

During a multisite, NIMH-sponsored clinical trial entitled, “Research Evaluating the Value of Augmentation of Medication by Psychotherapy” (REVAMP), we assessed the adequacy of prior antidepressant treatment in patients with chronic forms of major depressive disorder using the Antidepressant Treatment History Form (ATHF). We hypothesized that when compared to earlier studies treatment adequacy would not have increased over the past decade. We found that only 33% of the 801 subjects enrolled had ever had a prior adequate trial of antidepressant medication. Patients significantly more likely to have received prior adequate antidepressant trials were older, married, white, had a longer duration of illness, had more melancholic features or met criteria for the melancholic subtype or met lifetime criteria for panic disorder. The hypothesis that rates of treatment adequacy have not significantly increased over the past decade was supported. These results and the consistency of similar results over time point to the dire need for patient and provider education regarding the signs and symptoms of depression and its treatment.

A System-Based Approach to Depression Management in Primary Care Using the Patient Health Questionnaire-9

Primary care physicians are more likely to see patients with depression than with any other disorder except hypertension, and its management poses a challenge to busy primary care practices. The Patient Health Questionnaire-9, a simple self-administered tool of proven validity and reliability, is a commonly used screening instrument for depression in primary care practice. This review article provides a system-based approach to depression management using the Patient Health Questionnaire-9 to guide clinicians in the identification and treatment of depression and its follow-up care.

A randomized, single-blind, comparison of venlafaxine with paroxetine in elderly patients suffering from resistant depression

It is estimated that up to 45% of patients with depression do not have an adequate response to a first trial of antidepressant therapy with even higher reported rates for the elderly patients. To compare the efficacy and the tolerability of venlafaxine vs. paroxetine in elderly patients suffering from resistant major depression, who did not respond to at least two previous adequate trials of antidepressants. Patients entered an 8-week single-blind study. Patients were rated using the Clinical Global Impression Scale, Hamilton Rating Scale for Depression, and the Geriatric Depression Scale. Assessments were performed at baseline and on days 7, 14, 21, 28, 42 and 56. Side effects were recorded in a systemic manner. Thirty patients were included in the study, (17 women, 13 men; mean age=75.9 years, range: 68-83) and all had completed the 6-week trial. Mean dose of venlafaxine used was 165 mg/day (SD=73.8; range 75-300 mg). Mean dose of paroxetine used was 26 mg/day (SD=15.04; range 10-60 mg). Nine patients treated with venlafaxine (60%) and five patients treated with paroxetine (33%) remitted after 8 weeks of treatment. Four patients treated with venlafaxine and eight patients treated with paroxetine failed to respond. Significant improvement in Hamilton Rating Scale for Depression scores between baseline and endpoint were observed in both groups of patients. The mean Hamilton Rating Scale for Depression change for paroxetine was -12.5 and for venlafaxine -19.1 (P<0.05). The mean Geriatric Depression Scale change for paroxetine was -3.2 and for venlafaxine -6.0 (P<0.3). The mean Clinical Global Impression Scale change was -2.3 for paroxetine and -3.5 for venlafaxine (P<0.05). Venlafaxine was significantly superior to paroxetine on Clinical Global Impression Scale and Hamilton Rating Scale for Depression measures. Side effects were transient and did not differ between treatment groups. Elderly depressed patients resistant to previous treatments had responded to a trial of paroxetine or venlafaxine. Remission rates were higher for venlafaxine and tolerability was acceptable for both compounds.

Clinical Factors Associated With Treatment Resistance in Major Depressive Disorder

Very few studies have investigated clinical features associated with treatment-resistant depression (TRD) defined as failure of at least 2 consecutive antidepressant trials. The primary objective of this multicenter study was to identify specific clinical and demographic factors associated with TRD in a large sample of patients with major depressive episodes that failed to reach response or remission after at least 2 consecutive adequate antidepressant treatments. A total of 702 patients with DSM-IV major depressive disorder, recruited from January 2000 to February 2004, were included in the analysis. Among them, 346 patients were considered as nonresistant. The remaining 356 patients were considered as resistant, with a 17-item Hamilton Rating Scale for Depression score remaining greater than or equal to 17 after 2 consecutive adequate antidepressant trials. Cox regression models were used to examine the association between individual clinical variables and TRD. Among the clinical features investigated, 11 variables were found to be associated with TRD. We found anxiety comorbidity (p < .001, odds ratio [OR] = 2.6), comorbid panic disorder (p < .001, OR = 3.2) and social phobia (p = .008, OR = 2.1), personality disorder (p = .049, OR = 1.7), suicidal risk (p = .001, OR = 2.2), severity (p = .001, OR = 1.7), melancholia (p = .018, OR = 1.5), a number of hospitalizations > 1 (p = .003, OR = 1.6), recurrent episodes (p = .009, OR = 1.5), early age at onset (p = .009, OR = 2.0), and nonresponse to the first antidepressant received lifetime (p = .019, OR = 1.6) to be the factors associated with TRD. Our findings provide a set of 11 relevant clinical variables associated with treatment resistance in major depressive disorder that can be explored at the clinical level. The statistical model used in this analysis allowed for a hierarchy of these variables (based on the OR) showing that comorbid anxiety disorder is the most powerful clinical factor associated with TRD.

Vagus Nerve Stimulation for Severe Depression

&lt;p&gt;Treatment-resistant depression (TRD) typically involves insufficient response to at least one and often several adequate antidepressant therapy trials. The World Health Organization considers depression the leading cause of disability worldwide as measured by years lived with disability. Up to 30% of major depressive episodes do not respond to a series of treatments. TRD has a significant economic impact associated with both increased depression-related and general medical-related costs compared to non-resistant patients. &lt;/p&gt; &lt;h4&gt;ABOUT THE AUTHORS&lt;/h4&gt; &lt;p&gt;Jeffrey Rado, MD, is with the Department of Psychiatry, Rush University, Chicago, IL. Philip G. Janicak, MD, is Professor of Psychiatry, Rush University, Chicago, IL.&lt;/p&gt; &lt;p&gt;Address correspondence to: Philip G. Janicak, MD, 1720 W. Polk Street, Chicago, IL 60612; or email: &lt;a href="mailto:Philip_Janicak@rush.edu"&gt;Philip_Janicak@rush.edu&lt;/a&gt;.&lt;/p&gt; &lt;p&gt;Dr. Rado is a coinvestigator for Neuronetics Inc. Dr. Janicak is a grant recipient and consultant for Neuronetics Inc., developer of NeuroStar TMS (transcranial magnetic stimulation) System.&lt;/p&gt; &lt;h4&gt;EDUCATIONAL OBJECTIVES&lt;/h4&gt; &lt;ol&gt; &lt;li&gt;Discuss the rationale for the use of vagus nerve stimulations (VNS) in patients with depression and discuss the data from clinical trials of VNS in depression.&lt;/li&gt; &lt;li&gt;Demonstrate awareness of the most common side effects of VNS.&lt;/li&gt; &lt;li&gt;Describe the initiation and monitoring of depressed patients treated with VNS.&lt;/li&gt; &lt;/ol&gt;

An Open-Label Trial of Risperidone Augmentation for Refractory Anxiety Disorders

There is a paucity of data to support "next-step" treatments for the many patients with anxiety disorders who remain symptomatic after initial pharmacotherapy. Thirty patients with a primary diagnosis of an anxiety disorder-panic disorder (PD), social anxiety disorder (SAD), or generalized anxiety disorder (GAD)-refractory to initial pharmacotherapy with an adequate (or maximally tolerated) antidepressant and/or benzodiazepine trial of at least 8 weeks' duration prior to study initiation received open-label augmentation with flexibly dosed risperidone for 8 weeks. Participants were diagnosed using the Structured Clinical Interview for DSM-IV. Risperidone augmentation at a mean +/- SD dose of 1.12 +/- 0.68 mg/day (range, 0.25-3.00 mg/day) resulted in a significant reduction in anxiety symptoms across disorders as measured by the Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Anxiety (HAM-A) scores and for each disorder-specific primary outcome measure-the Panic Disorder Severity Scale, the Liebowitz Social Anxiety Scale, and HAM-A-in the intent-to-treat sample. Seventy percent (21/30) of participants completed the 8-week trial, with premature discontinuation due primarily to sedation and weight gain. Although conclusions are limited by the open-label, relatively brief nature of this trial, our data suggest that augmentation with low-dose risperidone may be a useful option for patients with PD, SAD, or GAD refractory to adequate initial intervention with antidepressants and/or benzodiazepines. Longer-term, controlled safety and efficacy data are needed to understand the place of risperidone augmentation in the algorithm of treatment options for refractory anxiety disorders.

Treatment resistance in unipolar depression: Is it an iatrogenic phenomenon caused by antidepressant treatment of patients with a bipolar diathesis?

Major depressive disorder is a common psychiatric illness that is considered generally treatable; however, there are some patients who fail to respond in spite of adequate trials of antidepressants. Clinical factors known to contribute to treatment resistance include psychiatric and physical comorbidity, undiagnosed bipolarity, and treatment non-adherence. There is also emerging evidence that the use of antidepressants in some 'unipolar' patients may lead to a pattern of progressive diminution of therapeutic response and ultimately treatment resistance. A large number of these patients may have a bipolar diathesis even though there are no symptoms of hypomanic, manic or mixed episodes. It is hypothesized that the widespread and injudicious use of antidepressants in patients with a bipolar diathesis might result in treatment-induced resistant depression. Furthermore, attempts to manage the antidepressant-led mood instability might cause increased utilisation of other psychotropic drugs including sedative/hypnotics, neuroleptics and mood stabilisers and contribute to polypharmacotherapy.

Intramuscular Testosterone Supplementation to Selective Serotonin Reuptake Inhibitor in Treatment-Resistant Depressed Men

Treatment-resistant depression is a persistent clinical problem. Exogenous testosterone therapy has psychotropic effects and has been proposed as an antidepressant supplement, although this strategy has received limited systematic study. The aim of the study was to examine the mood effects of testosterone supplementation to a serotonergic antidepressant in men with treatment-resistant depression. Twenty-six healthy adult men with major depressive disorder, partial or nonresponse to 2 adequate antidepressant trials during the current episode, and currently using a selective serotonin reuptake inhibitor were randomized under double-blind conditions to receive intramuscular injections of escalating doses of testosterone or placebo, in addition to their existing selective serotonin reuptake inhibitor regimen, for 6 weeks. The main outcome measure was the Hamilton Rating Scale for Depression score. The mean age was 46.4 +/- 10.8 years; mean total testosterone level, 417.5 +/- 197 ng/dL; mean baseline Hamilton Rating Scale for Depression score, 22.2 +/- 5.2; and median duration of the current depressive episode, 6.3 +/- 10.6 years. Hamilton Rating Scale for Depression scores decreased significantly in both testosterone (8.4) and placebo (7.4) groups. Antidepressant response, defined as a 50% decline in Hamilton Rating Scale for Depression score, was achieved by 53.8% (7/13) in the testosterone group and 23.1% (3/13) in the placebo group (P = 0.226). Both injectable testosterone and placebo supplementation to selective serotonin reuptake inhibitor were associated with improvement in mood; group differences were not distinguishable in this small sample of predominantly eugonadal men with treatment-resistant depression.

Efficacy of Electroconvulsive Therapy in Treatment-Resistant Bipolar Disorder

The response to electroconvulsive therapy for six bipolar patients after pharmacotherapy failure is discussed. Inclusion criteria were as follows: (1) bipolar mood disorder, manic, depressive or mixed episode (DSM-IV); (2) failure of pharmacotherapy, that is, for mania, manic episode unresponsive to at least 2 adequate antimanic trials for 6 weeks; and for bipolar depression, bipolar depressive episode unresponsive to at least 2 adequate antidepressant trials for 8 weeks. The patients underwent 12 bilateral sessions of ECT 3 times per week. Clinical response was considered a reduction of 50% or greater in the Young Mania Rating Scale (YMRS) and in the Hamilton Rating Scale for Depression-21 items (HAMD-21). Final YMRS <6 and HAMD-21 <8 defined remission. Six of the 9 referred patients consented to be submitted to ECT. Four were male, with ages ranging from 29 to 61 years, and their age at onset ranged from 19 to 49 years. Four showed psychotic features. All responded to ECT.

Nortriptyline for Treatment-Resistant Depression

Up to 30% of patients with major depression fail to respond to an antidepressant trial, with most taking a selective serotonin reuptake inhibitor (SSRI) as initial treatment. While the tricyclic antidepressants might be effective for SSRI nonresponders, they have been relegated to third- and fourth-line treatment. This study assesses the efficacy of nortriptyline for patients with treatment-resistant major depression. 92 patients with treatment-resistant DSM-III-R major depression, with resistance defined by at least 1, but no more than 5, well-documented adequate trials of antidepressants during the current episode, were treated openly with nortriptyline for 6 weeks. Patients were titrated up to full target doses of nortriptyline within 1 week, with target blood levels of 100 ng/mL. Response was defined as a 50% or greater decrease of baseline 17-item Hamilton Rating Scale for Depression score. We performed an intent-to-treat analysis with the last observation carried forward. Approximately 40% of patients were responders (N = 39) and 12% were remitters (N = 11) after 6 weeks of nortriptyline. Over a third of patients were unable to complete the trial. Nortriptyline was effective for over a third of patients with treatment-resistant depression, and nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants.

Vagus Nerve Stimulation (VNS™) for Treatment-Resistant Depression: Efficacy, Side Effects, and Predictors of Outcome

This open pilot study of vagus nerve stimulation (VNS™) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD28 measure, 34.0% for the Montgomery-Äsberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p = .0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.