Prakash S. Masand

Tolerability and adherence issues in antidepressant therapy.

BACKGROUND Despite the availability of effective antidepressants, recurrence and relapse rates for depression are high (up to 80%), treatment failures are common (40% to 60%), and as many as 20% of patients remain inadequately treated. Depression treatment guidelines are often not followed, and rates of nonadherence to treatment are high, with 28% of patients discontinuing antidepressant treatment within the first month and 44% discontinuing within 3 months of initiating therapy. OBJECTIVE The aim of this article was to summarize research on antidepressant therapy nonadherence and examine the limitations of strategies used to minimize adverse events (AEs) and improve treatment duration. METHODS A thorough search of the published literature from 1990 to the present was performed on MEDLINE and other search engines. The following search terms were used: tolerability, antidepressants, patient compliance, adherence, therapy, SSRIs, tricyclics, and other related terms focusing on specific agents. RESULTS Physician-specific issues represent some of the most important obstacles to adequate antidepressant therapy. Inadequate patient education, prescription of inappropriate medications or inadequate dosages, and lack of follow-up care are all issues the physician can control to improve patient adherence. Patient-specific issues include poor motivation (due to symptoms of depression) to continue therapy, failure to perceive a benefit, and concerns about cost of therapy. Medication-specific issues such as treatment-related AEs, delayed onset of action, complicated dosing or titration schedule, and subtherapeutic dosing also contribute to treatment discontinuation. Therapy with >/=I antidepressant and/or atypical antipsychotic may improve symptom control, but little evidence exists regarding efficacy and safety. Dosage reduction has been attempted to reduce events that may lead to patient discontinuation, but this may increase the risk of recurrent depressive episodes. CONCLUSIONS To maximize patient adherence to antidepressant therapy, it is necessary to combine adequate treatment duration, realistic patient expectations, and the right dose of an agent capable of treating the full range of symptoms while controlling for AEs.

Psychostimulants for Depression in Hospitalized Cancer Patients

The hospital charts of 59 hospitalized oncology patients who had been treated with either dextroamphetamine or methylphenidate for depression during a 5-year period at the Massachusetts General Hospital were examined. Eighty-three percent of the patients showed at least some improvement following psychostimulant treatment. Seventy-three percent of all patients demonstrated marked or moderate depressive symptom improvement. No significant differences in efficacy were noted between the two psychostimulants, or across psychiatric diagnostic categories for depression. The patients improved quickly, usually within the first 2 days of treatment. Ten percent of the patients experienced adverse reactions warranting discontinuation of the psychostimulants. Fifty-four percent of all patients had some appetite improvement. Anorexia was not observed as a treatment side effect. The authors conclude that psychostimulants are an effective and safe method of treatment for the depressed oncology patient.

Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise.

The precise mechanisms of pain perception and transmission in the central nervous system have not been fully elucidated. However, extensive data support a role for the monoamine neurotransmitters, serotonin and norepinephrine, in the modulation of pain. Experiments with animal models of pain indicate that noradrenergic interventions, and to a lesser extent serotonergic interventions, reduce pain-related behavior. This is supported by data from clinical trials in humans in which antidepressants have been shown to reduce pain and functional impairment in central and neuropathic pain conditions. These effects are particularly well-studied in trials with serotonin-norepinephrine reuptake inhibitors (SNRIs), which have provided a useful tool in the clinician’s arsenal, particularly considering the limitations of other classes of pain medications such as opioids, anti-inflammatories, and anticonvulsants (i.e., limited efficacy, safety and tolerability issues). Moreover, painful physical symptoms are frequently comorbid with major psychiatric disorders such as major depressive disorder and anxiety disorders. This paper reviewed and summarized the rationale and potential role of SNRIs for the control of pain including clinical and preclinical background. Currently evidence does not definitely support a role of the SNRIs, while limited data propose a putative promise of SNRIs in the treatment of pain related disorders including fibromyalgia and depressed patients with multiple somatic complaints. More researches are warranted to generalize currently available preliminary evidences.

Comorbidity of irritable bowel syndrome in psychiatric patients: a review.

Irritable bowel syndrome (IBS), a functional gastrointestinal disorder, is present in 10% to 20% of the U.S. adult population. The syndrome is best defined as chronic abdominal discomfort with changes in stool frequency, consistency, and passage, with associated symptoms such as abdominal bloating or presence of mucus in stools. Several studies have shown that up to 70% to 90% of patients with IBS who seek treatment have psychiatric comorbidity, most notably mood and anxiety disorders. Recent studies have shown a high prevalence of IBS in psychiatric patients who seek treatment, with a prevalence of 19% in schizophrenia, 29% in major depression, and 46% in panic disorder among other disorders. Our article reviews the comorbidity of IBS in psychiatric patients and discusses implications for treatment.

Partial Adherence to Antipsychotic Medication Impacts the Course of Illness in Patients With Schizophrenia: A Review

OBJECTIVE Although many clinicians acknowledge the occurrence of adherence problems with medication regimens among patients with schizophrenia, the problem shows no sign of improving. This may be because, in thinking about the issue, clinicians have tended to focus on patients who openly refuse or repeatedly discontinue treatment. While this description applies to only a minority of patients, in our experience, full adherence is rare; most patients are only partially adherent at best. This article examines the issue of adherence behavior in schizophrenia, focusing on the impact of partial adherence on treatment outcomes, particularly early in the course of illness. We also review potential strategies for managing the problem. DATA SOURCES Original research and review articles published in English from 1980 to 2008 were identified using the PubMed database, with the search terms schizophrenia or psychosis combined with compliance, noncompliance, partial compliance, adherence, nonadherence, or partial adherence. STUDY SELECTION Articles were selected by the authors on the basis of the hypotheses and/or data described. DATA SYNTHESIS Failure to adhere to medication as prescribed can have a major impact on the course of illness and treatment outcomes in patients with schizophrenia. Even relatively short gaps in medication coverage increase the risk of relapse. Problems with adherence are common early in the course of illness, when the consequences of relapse can be particularly devastating. CONCLUSION Clinicians in primary care and psychiatric settings need to be vigilant for signs of adherence problems among their patients and to act when necessary to prevent or alleviate the consequences of inadequate medication cover. Relapse prevention strategies, particularly for patients with early psychosis, should include ensuring that medication lapses are minimized or eliminated.

A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression.

We examined the efficacy and tolerability of augmentation with an extended release formulation of methylphenidate (OROS MPH, Concerta) in patients with major depression who were nonresponders or partial responders to antidepressants. Sixty subjects with treatment-resistant depression (TRD) participated in a 4-week, randomized, double-blind, placebo-controlled study of augmentation with methylphenidate (18-54 mg/d). The preexisting antidepressant dose was unchanged. The primary efficacy measure was change in the 21-item Hamilton Depression Rating Scale from randomization to end of treatment. Data were analyzed with intent-to-treat with last observation carried forward approach. There were no statistically significant differences between the methylphenidate (n = 30) and placebo (n = 30) groups in reduction in 21-item Hamilton Depression Rating Scale scores (drug, −6.9; placebo, −4.7) from baseline to end of treatment (F1,47 = 1.24, P = 0.22), although responders were numerically higher in the extended-release methylphenidate group (40.0%) than in the placebo group (23.3%). On the secondary efficacy measures of changes in Clinical Global Impression-Improvement and Severity scores and Beck Depression Inventory-Second Edition, the drug failed to separate from placebo, although the proportion of responders in the drug group were numerically higher than placebo. There were no significant differences in weight, heart rate, and blood pressure changes between the 2 groups. The common adverse events were loss of appetite, nausea, headache, and anxiety. The mean dose of drug was 34.2 mg/d. The study did not demonstrate a statistically significant benefit for augmentation with methylphenidate in TRD. Combination of methylphenidate with antidepressants was well tolerated. Adequately powered, randomized, controlled trials are necessary to fully evaluate the efficacy of extended-release methylphenidate in TRD.

Long-term side effects of newer-generation antidepressants: SSRIS, venlafaxine, nefazodone, bupropion, and mirtazapine

Anecdotal reports have suggested that the long-term use of selective serotonin reuptake inhibitors (SSRIs) may be associated with significant weight gain, sexual dysfunction, drug interactions, and discontinuation symptoms. Are these effects inevitable or can they be managed effectively with the appropriate interventions? In reviewing published, controlled clinical trials, it has been noted that many depressed patients experience weight gain during remission with or without treatment. Most antidepressants appear to produce a 3- to 4-kg weight gain after 6-12 months of therapy, which may be managed with nutritional counseling and exercise. The exception is mirtazapine, which appears to be associated with significant weight gain early in therapy. Antidepressant-induced sexual dysfunction is also common but may be managed with the addition of an antidote or substitution. Drug interactions are most common with fluvoxamine, nefazodone, and fluoxetine because these agents are more likely to affect the metabolism of commonly prescribed medications. It may be possible to prevent discontinuation symptoms with a cross taper to another antidepressant or by slowly tapering the antidepressant.

Use of Risperidone in Delirium: Case Reports

Traditionally, high-potency neuroleptics such as haloperidol have been used with success in the treatment of organic brain syndromes, but they have been associated with significant side effects such as EPS. We present the first case reports of a newer antipsychotic, risperidone, in the treatment of two delirious patients. Risperidone may prove to be an effective alternative to haloperidol in delirious patients, especially the elderly and the severely medically ill, who are more prone to adverse effects. Two case histories are presented, one of a 60-year-old man and the other of a 14-year-old boy in whom delirium was successfully treated with low doses of risperidone.

Improving adherence to antipsychotic pharmacotherapy.

OBJECTIVE To review the consequences of nonadherence to antipsychotic pharmacotherapy in patients with schizophrenia, as well as associated risk factors for nonadherence and methods of improving adherence. METHODS Review of the literature based on a MEDLINE search on the terms schizophrenia and adherence or compliance, limited to the English language, supplemented by the authors own knowledge of the topic. RESULTS Nonadherence to antipsychotic therapy is a common reason for relapse and rehospitalization of patients with schizophrenia and thus contributes to the high cost of treating psychoses, adverse events, and lack of insight. Comorbid substance abuse, little family involvement, and a poor clinician-patient relationship are among the risk factors for nonadherence. Patients with a negative attitude towards treatment, which can result from adverse events, are also more likely to be nonadherent. Strategies to improve adherence include optimizing antipsychotic therapy, minimizing adverse events, encouraging patient participation in psychoeducational programs, treating comorbid substance abuse disorders, involving family members in the treatment process, and forging a close therapeutic relationship with the patient. CONCLUSIONS Improving adherence is difficult but necessary for achieving optimal treatment outcomes. Careful selection of drug therapy, with emphasis on a drugs tolerability, combined with nonpharmacologic interventions, may help decrease nonadherence in patients with schizophrenia.

Oxidative/nitrosative stress and antidepressants: Targets for novel antidepressants ☆ ☆☆

The brain is an organ predisposed to oxidative/nitrosative stress. This is especially true in the case of aging as well as several neurodegenerative diseases. Under such circumstances, a decline in the normal antioxidant defense mechanisms leads to an increase in the vulnerability of the brain to the deleterious effects of oxidative damage. Highly reactive oxygen/nitrogen species damage lipids, proteins, and mitochondrial and neuronal genes. Unless antioxidant defenses react appropriately to damage inflicted by radicals, neurons may experience microalteration, microdysfunction, and degeneration. We reviewed how oxidative and nitrosative stresses contribute to the pathogenesis of depressive disorders and reviewed the clinical implications of various antioxidants as future targets for antidepressant treatment.