Mark Hyman Rapaport

Depression, visual acuity, comorbidity, and disability associated with age-related macular degeneration

OBJECTIVE To examine (1) the prevalence of depressive disorders in community-dwelling adults with advanced age-related macular degeneration (AMD) and (2) the relationship in this population between depression, visual acuity, the number of comorbid medical conditions, disability caused by vision loss as measured by the National Eye Institute-Vision Function Questionnaire (NEI-VFQ) and the vision-specific Sickness Impact Profile (SIPV), and disability caused by overall health status as measured by the Sickness Impact Profile-68 (SIP). DESIGN Analysis of cross-sectional baseline data from a randomized clinical trial. PARTICIPANTS Participants were 151 adults aged 60 and older (mean age, 80 years) with advanced macular degeneration whose vision was 20/60 or worse in their better eye. METHODS Subjects were interviewed using measures of depression, disability, and chronic medical conditions. Visual acuity was obtained. Nonparametric correlation analyses and linear regression analyses were performed. MAIN OUTCOME MEASURES Structured Clinical Interview for DSM-IV (SCID-IV), Geriatric Depression Scale (GDS), NEI-VFQ, SIPV, and SIP. RESULTS Of the participants, 32.5% (n = 49) met SCID-IV criteria for depressive disorder, twice the rate observed in previous studies of community-dwelling elderly. Over and above depression (GDS), visual acuity aided in prediction of the level of vision-specific disability (NEI-VFQ and SIPV). CONCLUSIONS Depressive disorder is a significant problem for the elderly afflicted with advanced macular degeneration. Further research on psychopharmacologic and psychotherapeutic interventions for depressed AMD patients is warranted to improve depression and enhance functioning. Over and above depression, visual acuity aided in predicting vision-specific disability. Treatment strategies that teach patients to cope with vision loss should be developed and evaluated.

Vagus nerve stimulation for treatment-resistant depression: A randomized, controlled acute phase trial

BACKGROUND Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

Clinical and Physiological Consequences of Rapid Tryptophan Depletion

We review here the rapid tryptophan depletion (RTD) methodology and its controversial association with depressive relapse. RTD has been used over the past decade to deplete serotonin (5-hydroxy-tryptamine, or 5-HT) in humans and to probe the role of the central serotonin system in a variety of psychiatric conditions. Its current popularity was stimulated by reports that RTD reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) in remitted patients with a history of depression but not in patients treated with antidepressants which promote catecholaminergic rather than serotonergic neurotransmission (such as tricyclic antidepressants or buproprion). However, RTD has inconsistent effects in terms of full clinical relapse in depressed patients. Pooling the data from all published reports, patients who are either unmedicated and/or fully remitted are much less likely to experience relapse (7 of 61, or ∼9%) than patients who are recently medicated and partially remitted (63 of 133, or ∼47%; although, the numbers here may reflect patient overlap between reports). Recently remitted patients who have been treated with non-pharmacological therapies such as total sleep deprivation, electroconvulsive therapy, or bright light therapy also do not commonly show full clinical relapse with RTD. We briefly review RTD effects in other psychiatric disorders, many of which are treated with SSRIs. There is accumulating evidence to suggest that RTD affects central serotonergic neurotransmission. Nevertheless, many questions remain about the ability of RTD to reverse the beneficial effects of SSRIs or MAOIs, or to induce symptoms in unmedicated symptomatic or asymptomatic patients.

Minor depressive disorder and subsyndromal depressive symptoms: functional impairment and response to treatment

BACKGROUND This study quantifies functional impairment and depressive symptomatology in patients with minor depressive disorder (MinD) and subsyndromal depressive symptomatology (SSD) before and after 8 weeks of treatment with fluvoxamine. Study patients were compared and contrasted with archival data from a sample of the general population measured by the Medical Outcome Survey Short Form 36. METHOD Fifteen patients with MinD and 15 patients with SSD were identified from primary care clinics, referrals and newspaper advertisements. Patients signed informed consent and were offered open label treatment with fluvoxamine 25-100 mg/day. Patients were seen biweekly and measures of functional impairment and depressive symptomatology were gathered systematically. RESULTS MinD and SSD were associated with dysfunction and disability when compared to archival normative data from the general population. Eight week treatment with fluvoxamine was associated with a substantial decrease in depressive symptomatology and a normalization of psychosocial functioning. CONCLUSION This is the first study to quantify functional impairment and the severity of depressive symptomatology in a clinical sample of patients with MinD and SSD, and to demonstrate that treatment with a selective serotonin reuptake inhibitor decreases depressive symptomatology and improves psychosocial functioning. Placebo-controlled double-blind confirmation of these preliminary observations seems warranted.

Moclobemide in social phobia: A controlled dose-response trial

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

Quality of Life: The Ultimate Outcome Measure of Interventions in Major Depressive Disorder

Background: Quality‐of‐life (QOL) assessment and improvement have recently been recognized as important components of health care, in general, and mental health care, in particular. Patients with major depressive disorder (MDD) have a significantly diminished QOL. Methods: Using a Medline search of relevant keywords for the past 26 years, this article reviews the empirical literature to provide information regarding QOL measurement, impairment, impact of comorbidity, and treatment effects in MDD. Results: Studies showed that QOL is greatly affected by depression. Severity of depression is also a major contributor to further reduction in QOL when depression is comorbid with other psychiatric and medical disorders. Treatment for MDD has been shown to improve QOL in the acute treatment phase, but QOL remains low compared to healthy controls even when symptoms are in remission following treatment. Conclusions: Patients with MDD suffer from poor QOL even after reduction of symptom severity. Clinicians should therefore include QOL assessment as an important part of treating depression. More research is needed to examine the factors contributing to poor QOL in MDD and to develop interventions to ameliorate it. Additionally, future treatment studies of MDD with or without comorbid disorders should track QOL as the ultimate outcome measure of treatment success.

Effects of Risperidone Augmentation in Patients with Treatment-Resistant Depression: Results of Open-Label Treatment Followed by Double-Blind Continuation

Approximately one-third of persons with depression do not respond to antidepressant monotherapy. Studies suggest that atypical antipsychotic augmentation may benefit these patients. We investigated the longer-term efficacy of risperidone augmentation of serotonin-selective reuptake inhibitor treatment for resistant depression. In 57 in- and outpatient centers in three countries, we conducted a three-phase study with 4–6 weeks of open-label citalopram monotherapy, 4–6 weeks of open-label risperidone augmentation, and a 24-week double-blind, placebo-controlled discontinuation phase. A total of 489 patients with major depressive disorder and 1–3 documented treatment failures entered the citalopram monotherapy phase (20–60 mg/day). Patients with <50% reduction in HAM-D-17 scores entered the risperidone augmentation phase (0.25–2.0 mg/day). Patients with HAM-D-17⩽7 or CGI-S⩽2 were randomized to risperidone or placebo augmentation. The primary outcome was time to relapse during the double-blind phase. During citalopram monotherapy, 434 patients had <50% HAM-D-17 reduction; 299 (68.9%) were fully nonresponsive (<25% reduction) and 135 were partially nonresponsive (25–49% reduction). Of the 386 nonresponders who entered the augmentation phase, 243 remitted and 241 entered the double-blind phase. Median time to relapse was 102 days with risperidone augmentation and 85 days with placebo (NS); relapse rates were 53.3 and 54.6%, respectively. In a post hoc analysis of patients fully nonresponsive to citalopram monotherapy, median time to relapse was 97 days with risperidone augmentation and 56 with placebo (p=0.05); relapse rates were 56.1 and 64.1%, respectively (p⩽0.05). Open-label risperidone augmentation substantially enhanced response in treatment-resistant patients, but the longer-term benefits of augmentation were not demonstrated in this study.

C-reactive protein levels in schizophrenia: a review and meta-analysis.

There is an impression in the literature that schizophrenia is associated with increased inflammation, including abnormal blood levels of the acute phase reactant C-reactive protein (CRP). We performed a meta-analysis of blood CRP levels to estimate the overall effect size, as well as a pooled analysis of the prevalence of an elevated CRP level in patients with schizophrenia and related disorders. We identified articles by searching PubMed, PsycInfo, and ISI, and the reference lists of identified studies. Eight studies met the inclusion criteria for the meta-analysis, and five studies were included in the pooled analysis. CRP levels were significantly increased in patients compared to controls (effect size=0.45, 95% confidence interval 0.34-0.55, p<0.001). There was a 28% prevalence of an elevated CRP level in patients with schizophrenia and related disorders. Our results support a growing body of literature that schizophrenia is associated with increased inflammation, although many studies did not control for potential confounding factors such as BMI and smoking. Given the high prevalence of elevated CRP, metabolic syndrome, and premature cardiovascular mortality, our findings also suggest that measurement of blood CRP levels may be germane to the clinical care of patients with schizophrenia and related disorders.

Omega-3 Fatty Acid Augmentation of Citalopram Treatment for Patients with Major Depressive Disorder

Objective The objective of this study was to explore the efficacy of combination therapy with citalopram plus omega-3 fatty acids versus citalopram plus placebo (olive oil) in the initial treatment of individuals with major depressive disorder (MDD). We hypothesized that combination therapy would lead not only to greater efficacy but also to a more rapid onset of therapeutic response. Methods Forty-two subjects participated in this 9-week randomized, masked, placebo-controlled study of combination therapy (two 1 g capsules containing a blend of 900 mg of eicosapentaenoic acid, 200 mg of and docosahexaenoic acid, and 100 mg of other omega-3 fatty acids twice daily plus citalopram) versus monotherapy (two 1 g capsules of olive oil per day plus citalopram) treatment of MDD. Results The combination therapy demonstrated significantly greater improvement in Hamilton Depression Rating scale scores over time (F = 7.32; df 1,177; P = 0.008) beginning at week 4 (t = −2.48; df 177; P = 0.014). Conclusions Combination therapy was more effective than monotherapy in decreasing signs and symptoms of MDD during the 8 weeks of active treatment; however, combination therapy did not seem to enhance the speed of the initial antidepressant response. These findings suggest that there may be an advantage to combining omega-3 fatty acids with a selective serotonin uptake inhibitor in the initial treatment of individuals with MDD. A larger definitive study is warranted.