Can long-term thiamine treatment improve the clinical outcomes of myotonic dystrophy type 1?

Myotonic dystrophy type 1,also known as Steinert's disease,is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles,the eyes,and the endocrine system.Thiamine(vitamin B1) is a cofactor of fundamental enzymes involved in the energetic cell metabolism; recent studies described its role in oxidative stress,protein processing,peroxisomal function,and gene expression.Thiamine deficiency is critical mainly in the central and peripheral nervous system,as well as in the muscular cells.Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study.We described two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months.We evaluated the patients using the grading of muscle strength according to Medical Research Council(MRC),the Muscular Impairment Rating Scale(MIRS),and the Modified Barthel index.High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology,particularly the muscle strength evaluated with the MRC scale,and the patients' activities of daily living using the Modified Barthel Index.At the end of treatment,the MRC score was 5 in the proximal muscles and 2–4 in the distal muscles(the MRC score before the treatment was 3–4 and 1–3,respectively).The MIRS grade improved by 25% compared to baseline for both patients.In patient #1,the Modified Barthel Index improved by 44%,and in patient #2 by 29%.These findings suggest that clinical outcomes are improved by long-term thiamine treatment.     

Can long-term treatment with antidepressant drugs worsen the course of depression?

BACKGROUND: The possibility that antidepressant drugs, while effectively treating depression, may worsen its course has received inadequate attention. METHOD: A review of the literature suggesting potential depressogenic effects of long-term treatment with antidepressant drugs was performed. A MEDLINE search was conducted using the keywords tolerance, sensitization, antidepressive agents, and switching. This was supplemented by a manual search of Index Medicus under the heading "antidepressant agents" and a manual search of the literature for articles pointing to paradoxical effects of antidepressants. RESULTS: A number of reported clinical findings point to the following possibilities: very unfavorable long-term outcome of major depression treated by pharmacologic means, paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances, antidepressant-induced switching and cycle acceleration in bipolar disorder, occurrence of tolerance to the effects of antidepressants during long-term treatment, onset of resistance upon rechallenge with the same antidepressant drug in a few patients, and withdrawal syndromes following discontinuation of mood-elevating drugs. These phenomena in susceptible individuals may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effects of a drug and may result in loss of clinical effect. When drug treatment ends, these processes may operate unopposed, at least for some time, and increase vulnerability to relapse. CONCLUSION: The possibility that antidepressant drugs may worsen the course of depression needs to be tested, even though its scientific exploration is likely to encounter considerable methodological and ideological difficulties. The clinical implications of this hypothesis in depression are considerable. Antidepressant drugs are crucial in the treatment of major depressive episodes. However, appraisal of paradoxical effects that may occur in susceptible patients during long-term treatment may lead to more effective use of the drugs.     

Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: a randomized open-label trial

Rationale

Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2 weeks and early treatment nonresponse is a predictor of subsequent nonresponse.

Objectives

We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy.

Method

Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50 mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100 mg, whereas sertraline was switched to paroxetine 20-40 mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8.

Results

Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001).

Conclusions

Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression.     

Observation of treatment of depression in primary care setting in first week - what happens in first week of treatment with antidepressants?

Depression is frequently diagnosed and treated by general practicioners. In observational study we investigated the influence of the severity of depressive and anxiety symptoms on the frequency of patients' questions about mental disorder and their tendency to misinterpret the signs and symptoms of depression as side effects of medication. In 60 public health centers across Slovenia a total of 422 patients with depression treated with paroxetine were included. After one week of treatment one quarter of patients reported adverse effects and 15% of these patients misinterpreted signs of depression and anxiety for adverse effects. These patients tend to be more anxious and more depressed at the beginning of treatment. Half of them could not accept the explanation of their misinterpretation. A total of 55% patients had additional questions about illness at the second visit and these patients were also more anxious and more depressed at the beginning of treatment.     

Does enhanced social support improve outcomes for problem drinkers in guided self-change treatment?

Although social support has been repeatedly identified as a strong correlate of recovery from alcohol problems, enhancing social support has seldom been a focus of treatment research. Married problem drinkers who were willing to have their spouses involved in their treatment were randomly assigned among two brief outpatient treatment conditions: directed social support (DS, n = 28) and natural social support (NS, n = 28). In both conditions the treatment in which the problem drinkers participated was an identical program of guided self-change, a cognitive-behavioral motivational intervention involving an assessment and four individual treatment sessions. Problem drinkers' spouses each attended two individual counseling sessions where they were informed about the counseling procedures. The conditions differed in that spouses in the DS group were encouraged to play an active role in helping their partner by being supportive and particularly by reacting to relapse episodes in a manner consistent with a relapse prevention model. One year follow-up found that participants in both groups improved significantly from pretreatment to the end of treatment, and that the gains were maintained over follow-up. The two groups did not differ significantly from one another at any point in time. Possible explanations for the results include that (a) the baseline level of social support in this population may have created a ceiling effect, and (b) the prognosis for this population may be so positive that it is difficult to demonstrate significant enhancement of outcomes.     

How should efficacy be evaluated in randomized clinical trials of treatments for depression?

The present system of conducting studies of promising antidepressant therapies has evolved through the collaborative efforts of government, industry, and academicians and is costly and inefficient. At least one third of the published clinical trials of approved antidepressants are negative for efficacy, which can be partly explained by the clinical and neurobiological heterogeneity of the depressive disorder and partly because of methodological inadequacies. Unfortunately, too little attention is given to ensuring the reliability of diagnoses and dependent measures, sample sizes are seldom large enough to detect modest yet honestly significant differences, and too many trials are pursued before dose-response characteristics are fully understood. At present, the only data beyond 1 year of treatment--and the only evidence about protection against recurrent depression--come during postmarketing or phase 4 of the drug development process. Moreover, efficacy data for depressed children and adolescents, bipolar depression, psychotic depression, dysthymia, and frail or medically ill elderly patients are rarely available at the time a drug is introduced. Thus, it is remarkable how little clinicians know about a new antidepressant at the time it is first approved for general use. Within a research strategy, tactics that ensure reliability, encourage attention to adherence, and lessen attrition at the outset of a study will increase the power and design sensitivity of a particular trial. Additionally, the issues of research funding-including division of the research pie-and the relationship of the Food and Drug Administration and investigators to the pharmaceutical industry and the National Institute of Mental Health need to be revisited. Finally, extension of a compound's patent life might be considered to expand the necessary postmarketing research. This article describes the process of conducting the clinical trials that support a New Drug Application, discusses issues in evaluating efficacy, and offers suggestions for modifying and improving the drug development process so that clinicians can better judge new drugs.     

Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice?

OBJECTIVE: The methods used to evaluate the efficacy of antidepressants differ from treatment for depression in routine clinical practice. The rigorous inclusion/exclusion criteria used to select subjects for participation in efficacy studies potentially limit the generalizability of these trials' results. It is unknown how much impact these criteria have on the representativeness of subjects in efficacy trials. This study estimated the proportion of depressed patients treated in routine clinical practice who would meet standard inclusion/exclusion criteria for an efficacy trial. METHOD: A total of 803 individuals, aged 16--65 years, who were seen at intake at an outpatient practice underwent a thorough diagnostic evaluation, including the administration of semistructured diagnostic interviews; 346 patients had current major depression. Common inclusion/exclusion criteria used in efficacy studies of antidepressants were applied to the depressed patients to determine how many would have qualified for an efficacy trial. RESULTS: Approximately one-sixth of the 346 depressed patients would have been excluded from an efficacy trial because they had a bipolar or psychotic subtype of depression. The presence of a comorbid anxiety or substance use disorder, insufficient severity of depressive symptoms, or current suicidal ideation would have excluded 86.0% (N=252) of the remaining 293 outpatients with nonpsychotic unipolar major depressive disorder from an antidepressant efficacy trial. CONCLUSIONS: Subjects treated in antidepressant trials represent a minority of patients treated for major depression in routine clinical practice. These results show that antidepressant efficacy trials tend to evaluate a subset of depressed individuals with a specific clinical profile.     

Is alpha wave neurofeedback effective with randomized clinical trials in depression? A pilot study

Frontal asymmetric activation has been proposed to be the underlying mechanism for depression. Some case studies have reported that the enhancement of a relative right frontal alpha activity by an asymmetry neurofeedback training leads to improvement in depressive symptoms. In the present study, we examined whether a neurofeedback training designed to increase the relative activity of the right frontal alpha band would have an impact on symptoms of depressive subjects suffering from emotional, behavioral, and cognitive problems. Our results indicated that the asymmetry neurofeedback training increased the relative right frontal alpha power, and it remained effective even after the end of the total training sessions. In contrast to the training group, the placebo control group did not show a difference. The neurofeedback training had profound effects on emotion and cognition. First, we replicated earlier findings that enhancing the left frontal activity led to alleviation of depressive symptoms. Moreover, cognitive tests revealed that the asymmetry training improved performance of executive function tests, whereas the placebo treatment did not show improvement. We preliminarily concluded that the asymmetry training is important for controlling and regulating emotion, and it may facilitate the left frontal lobe function.     

No melancholia in poststroke depression? A phenomenologic comparison of primary and poststroke depression

The present study aimed at the phenomenologic comparison of depressive symptoms in elderly patients with poststroke depression (PSD) or primary depression (depression without a known neuropathology). We investigated 20 patients with PSD and 41 patients with primary depression. A structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, self- and observer-based depression rating scales, a clinical neurologic examination, and neuroradiologic analysis based on standardized computed tomographic scan analysis were applied. The Cornell Depression Scale was used to compare mood-related signs, behavioral disturbances, physical signs, disturbances of cyclic signs, and ideational disturbances in both groups of patients. Those with PSD exhibited no melancholia and fewer cyclic and ideational disturbances but more physical signs of depression. These findings are in line with those of endocrinologic studies. Differences between both groups of patients indicate that careful considerations and further research are needed before treatment strategies developed for and evaluated in patients with primary depression are applied to patients with PSD.     

Can computer-assisted cognitive remediation improve employment and productivity outcomes of patients with severe mental illness? A meta-analysis of prospective controlled trials

BackgroundComputer-assisted cognitive remediation (CACR) has been demonstrated to enhance cognition of patients with severe mental illness (SMI). Patients with improved cognitive skills may find it easier to be employed, and the ability to maintain employment is an important sign of recovery.AimTo assess whether CACR is an effective method to enhance work-related outcomes in patients with SMI.MethodProspective controlled trials evaluating CACR on productivity outcomes were systematically identified from the OVID databases. Employment rates, total days of work in a year, and total annual earnings were defined as the productivity outcomes.ResultsNine trials were published between 2005 and 2014 and were conducted in the United States, Germany, Italy, Singapore and Japan. A total of 740 patients with mean age of 36.4 years were included. The duration of CACR ranged from 2 months to 2 years, and the patients were followed-up from 1 year to 3 years. Patients receiving CACR showed 20% higher employment rate (95% CI = 5%–35%), worked 19.5 days longer in a year (95% CI = 2.5–36.6 days), and earned US$959 more in total annual earnings (95% CI = US$285 to US$1634) than those not receiving CACR.ConclusionCACR can enhance productivity outcomes for patients with SMI, including higher employment rate, longer duration of work and higher income. The economic benefit of CACR can enhance the quality of life for patients with SMI, and may reduce financial burden on the health and welfare system. Therefore, CACR can be recommended and incorporated into regular vocational rehabilitation programs.     

Are antidepressants effective in the acute and long-term treatment of depression? Sic et Non

The efficacy of antidepressant treatment of major depression remains a matter of controversy. A review of acute treatment studies suggests that for relatively more severe episodes of major depression, antidepressants are superior to treatment in the "placebo group;" however, there are numerous methodological confounds in the available literature. (Some recent, preliminary evidence suggests that antidepressants may also be of benefit in some less severely depressed populations).There is moderately strong evidence that, compared with placebo, maintenance antidepressant treatment reduces six-month relapse rates in major depression; however, it is less clear that antidepressants prevent actual recurrence of depression in the longer term. There is evidence of both over-use and under-use of antidepressant treatment, and there appears to be a "mismatch" between diagnosis and optimal treatment of depression in some clinical settings. Better designed studies are needed to resolve these uncertainties and to investigate such putative conditions as "oppositional tolerance" to long-term antidepressant treatment. The author advocates a conservative approach to antidepressant treatment, as well as a substantially extended "tapering" period when antidepressants are discontinued.     

Does adding psychotherapy to pharmacotherapy improve social functioning in the treatment of outpatient depression?

The existence of an overall association between severity of depression and level of social functioning is well documented. To increase the probability of a long-term recovery, a normal level of social functioning is essential. It is currently unknown whether combined therapy has a better outcome than pharmacotherapy with regard to social functioning. In a 6-month randomized clinical trial in outpatients with major depression, all patients studied had a baseline score of at least 14 points on the 17-item Hamilton Depression Rating Scale (HDRS). The two conditions consist of pharmacotherapy (PhT) (N=84) and combined therapy (CoT), pharmacotherapy plus 16 sessions of short psychodynamic supportive psychotherapy (N=83). Efficacy was assessed using the 17-item HDRS, the Clinical Global Impression (CGI) Severity and Improvement scales, the Depression subscale of the Symptom Checklist-90 (SCL-90), the Quality of Life Depression Scale (QLDS), more the Groningen Social Disability Schedule (GSDS). Severity of depression decreased significantly (on the SCL-90 Depression subscale and the QLDS) more in the CoT condition. A larger improvement in social functioning was demonstrated for remitted patients than for nonremitted patients. The number of dimensions of social functioning that had improved significantly was higher in CoT than in PhT. There was a moderate advantage of the CoT condition on both depressive symptoms and level of social functioning in comparison with PhT. We also found a positive association between depression severity and level of social functioning.