Practical management of treatment-resistant depression

Patients receiving antidepressant monotherapy may be partially or totally resistant to treatment in 10 to 30 percent of cases. In patients who have experienced only partial treatment results, the clinician should first consider optimizing antidepressant dosage or lengthening therapy. Antidepressant drug substitution should generally be reserved for use in patients who haven't responded at all (nonresponders). Combining two or more antidepressants is generally not recommended, as this approach may obscure adequate monotherapy evaluation and lead to significant adverse effects or drug-drug interactions. Use of electroconvulsive therapy is recommended in patients with psychotic and severe refractory depression. Augmentation therapy is often efficacious in patients who exhibit a partial antidepressant response. Lithium and thyroid hormone have been the most extensively studied augmentative agents but, more recently, pindolol and buspirone have also been used for this purpose.     

Mindfulness-based cognitive therapy to prevent relapse in recurrent depression.

For people at risk of depressive relapse, mindfulness-based cognitive therapy (MBCT) has an additive benefit to usual care (H. F. Coelho, P. H. Canter, & E. Ernst, 2007). This study asked if, among patients with recurrent depression who are treated with antidepressant medication (ADM), MBCT is comparable to treatment with maintenance ADM (m-ADM) in (a) depressive relapse prevention, (b) key secondary outcomes, and (c) cost effectiveness. The study design was a parallel 2-group randomized controlled trial comparing those on m-ADM (N = 62) with those receiving MBCT plus support to taper/discontinue antidepressants (N = 61). Relapse/recurrence rates over 15-month follow-ups in MBCT were 47%, compared with 60% in the m-ADM group (hazard ratio = 0.63; 95% confidence interval: 0.39 to 1.04). MBCT was more effective than m-ADM in reducing residual depressive symptoms and psychiatric comorbidity and in improving quality of life in the physical and psychological domains. There was no difference in average annual cost between the 2 groups. Rates of ADM usage in the MBCT group was significantly reduced, and 46 patients (75%) completely discontinued their ADM. For patients treated with ADM, MBCT may provide an alternative approach for relapse prevention. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Progressive resistance to a selective serotonin reuptake inhibitor but not to cognitive therapy in the treatment of major depression.

Recent research suggests that there may be a reduction in therapeutic response after multiple administrations of antidepressant drug (AD) therapy in patients with major depressive disorder. This study assessed the response to AD therapy and cognitive therapy (CT) of patients with a history of prior AD exposures. A sample of 240 patients with moderate-to-severe major depressive disorder entered a randomized controlled trial comparing pharmacotherapy with paroxetine to CT. Treatment was administered for 16 weeks. History of prior AD exposure was assessed with structured interviews, self-report, and medical records. Analyses were conducted using hierarchical linear models on the intent-to-treat sample. After controlling for various demographic and clinical factors, more prior AD exposures predicted poor response to paroxetine therapy but not to CT, as measured by the Hamilton Rating Scale for Depression (Hamilton, 1960; Williams, 1988). Whereas CT outcome was not significantly related to the number of prior AD exposures, a higher number of prior AD exposures was significantly associated with a lower response to paroxetine. If these findings are replicated in methodologically rigorous studies of paroxetine and other antidepressants, CT should be recommended, in preference to AD, for patients with multiple prior AD exposures. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of readiness to change in response to treatment of adolescent depression.

The effect of readiness to change on treatment outcome was examined among 332 adolescents (46% male, 74% Caucasian), ages 12 through 17 years (M = 14.6, SD = 1.5), with major depressive disorder who were participating in the Treatment for Adolescents With Depression Study (TADS). TADS is a randomized clinical trial comparing the effectiveness of fluoxetine (an antidepressant medication), cognitive–behavioral therapy, their combination, and a pill placebo. An abbreviated Stages of Change Questionnaire was used to obtain 4 readiness to change scores: precontemplation, contemplation, action, and maintenance. The association between each readiness score and depression severity across 12 weeks of acute treatment for depression, as measured by the Children’s Depression Rating Scale—Revised, was examined. Although treatment response was not moderated by any of the readiness scores, baseline action scores predicted outcome: Higher action scores were associated with better outcome regardless of treatment modality. Furthermore, treatment effects were mediated by change in action scores during the first 6 weeks of treatment, with increases in action scores related to greater improvement in depression. Assessing readiness to change may have implications for tailoring treatments for depressed adolescents. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Psychopharmacologic treatment of depression in the medically ill

Appropriate selection of an antidepressant agent in medically ill patients requires a careful risk-benefit assessment matching the pharmacokinetic and pharmacodynamic properties of the drug being considered against the patient's physiological vulnerabilities, potential for drug interactions, and primary symptoms of the patient's depression. While in the past antidepressant drug selection was limited by the almost sole availability of the tricyclic antidepressants, newer drugs such as selective serotonin reuptake inhibitors, bupropion, and venlafaxine have vastly simplified treating depression in the medically ill. In refractory cases of depression in patients with medical illness, electroconvulsive therapy can be used with appropriate anesthetic management.     

Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the acute treatment of adults with major depression.

Antidepressant medication is considered the current standard for severe depression, and cognitive therapy is the most widely investigated psychosocial treatment for depression. However, not all patients want to take medication, and cognitive therapy has not demonstrated consistent efficacy across trials. Moreover, dismantling designs have suggested that behavioral components may account for the efficacy of cognitive therapy. The present study tested the efficacy of behavioral activation by comparing it with cognitive therapy and antidepressant medication in a randomized placebo-controlled design in adults with major depressive disorder (N = 241). In addition, it examined the importance of initial severity as a moderator of treatment outcome. Among more severely depressed patients, behavioral activation was comparable to antidepressant medication, and both significantly outperformed cognitive therapy. The implications of these findings for the evaluation of current treatment guidelines and dissemination are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pharmacologic management of depression in the elderly

Depression, the most common geriatric psychiatric disorder, is a disabling mood disorder that impairs one's well-being and may even threaten a sufferer's life. Severely depressed elderly persons are more likely to kill themselves than individuals in any other age group. However, geriatric depression is, for the most part, a treatable and manageable illness. Antidepressant medication can be very effective in treating major depressive disorder (MDD). Because age-related physical changes in the elderly produce pharmacokinetics that are often different than that experienced by younger adults, different doses are often necessary. This article summarizes recommendations for selecting and initiating appropriate antidepressant therapy in elderly persons suffering from MDD. The benefits and drawbacks of tricyclic antidepressant agents, and other atypical antidepressant agents are discussed. Phases of treatment, drug selection, dosing, and educational tips for pharmacotherapy are presented.     

Pain after groin hernia repair

Depression is one of the most common psychiatric illnesses. Its influence on brain perfusion has been demonstrated, but conflicting data exist on follow-up after drug treatment. The aim of our study was to evaluate the effects of antidepressant drugs on regional cerebral blood flow (rCBF) in patients with depression after 3 weeks and 6 months of drug therapy. Clinical criteria for depression without psychosis were met according to psychiatric evaluation. Severity of depression was evaluated with the Hamilton Depression Rating Scale (HAMD) before every scintigraphic study. rCBF was assessed using technetium-99m bicisate (Neurolite) brain single-photon emission tomography in nine patients with severe depression before the beginning of antidepressant drug therapy and 3 weeks and six months after initiation of therapy. Only patients with no change in antidepressant medication during the study were included. No antipsychotic drugs were used. Cerebellum was used as the reference region. rCBF was evaluated for eight regions in each study in three consecutive transversal slices. Follow-up studies were compared with the baseline study. The mean HAMD score was 25.5 points initially, 16 at the second examination and 8.8 after 6 months. Global CBF was decreased compared with the reference region in drug-free patients. Perfusion of left frontal and temporal regions was significantly lower (P < 0.005) in comparison with the contralateral side. After therapy, a moderate decrease in perfusion was seen in the right frontal region (P < 0.05). Perfusion decreased further after 6 months in the right frontal (P < 0.005) and temporal regions (P < 0.01). The highly significant asymmetry in perfusion between the left and right frontal and temporal lobes almost disappeared during treatment. Our findings implicate dysfunction of the frontal and temporal cortex in clinically depressed patients before specific drug treatment. Clinical improvement and decreases in HAMD score after 3 weeks and after 6 months reflect the treatment effect on mood-related rCBF changes.     

Alternative approaches to refractory depression in bipolar illness

Thus, there appears to be a large variety of approaches to refractory bipolar depression. In contrast to several decades ago, wherein augmentation of lithium with antidepressants and neuroleptics was essentially the only treatment mode available, a panoply of treatment options now exist. However, their relative efficacy in different illness subtypes and stages remains to be better delineated, as do their optimal sequencing and use in combination in individual patients. It is the opinion of these authors and many of our colleagues in the field that initial use of several mood stabilizer drugs in combination may have a preferable long-term outcome in some rapid cycling patients, compared with the immediate use of a unimodal antidepressant with an inadequate single mood stabilizer, although this remains to be systematically studied. The use of thyroid augmentation strategies would appear to have merit in relationship to not only the potential treatment of lithium-related hypothyroidism, but also in augmenting antimanic and antidepressant effects. As one moves toward some of the complex combination treatment strategies discussed in this chapter, one has to be particularly careful about drug interactions and their potential for toxicity as well as therapeutic effects. Perhaps a prevailing guideline would be to use these agents more carefully in combination therapy than in monotherapy, with slow upward titration of dose to individual patients' side effects thresholds, even in preference to targeting of conventional blood level windows. In this way, side effects can be avoided during the assessment of complex combination regimens. In addition, one should be aware of potential pharmacokinetic interactions. For example, with the addition of valproate to carbamazenine, one should reduce the dose of carbamazepine, as valproate will not only increase the free fraction of carbamazepine based on displacement of protein binding, but will lead to increased accumulation of carbamazepine-10,11-epoxide. This epoxide is not measured in conventional assays but could contribute to the side effects profile (Ketter and Post, 1994). Similarly, valproate will markedly increase blood levels of lamotrigine; the starting dose of this agent should be substantially lower than conventional dosage when these two drugs are used in combination. We suggest the utility of detailed mapping with a formal system-such as the Life Chart Methodology (LCM) (Leverich and Post, 1996)-of mood fluctuation vs. medications in order to optimize and rationalize complex combination therapy. In this way, not only can the nuances of partial response be better defined, but also basic decisions about the therapeutic index and relative likelihood of response can be more readily assessed. We have discussed the other merits of the life chart method as an important clinical treatment tool as well as a research tool in other venues, but reemphasize its potential great importance in the treatment of refractory cyclic bipolar patients, in whom an initial period of remission of depression may, in many instances, be as likely attributable to the natural course of illness as the current intervention being offered. As such, it behooves the clinician to have a systematic database for the more subtle issues of dose titration and sequential addition of medications in complex combination regimens. In the face of inefficiency to one combination strategy, how one moves to the next strategy remains a highly individualized, clinically-based algorithm. We suggest the potential utility of moving towards a new set of mood stabilizers and then repeating some of the unimodal antidepressant additions and augmentation trials in an attempt to overcome refractory depression. Refractory depression in bipolar patients should be viewed as a medical emergency in light of the high potential for suicide in the illness in general (Chen and Dilsaver, 1996) and in patients who have either sustained or episodic refracto     

Relationship of posttreatment decentering and cognitive reactivity to relapse in major depression.

Z. V. Segal et al. (2006) demonstrated that depressed patients treated to remission through either antidepressant medication (ADM) or cognitive-behavioral therapy (CBT), but who evidenced mood-linked increases in dysfunctional thinking, showed elevated rates of relapse over 18 months. The current study sought to evaluate whether treatment response was associated with gains in decentering-the ability to observe one's thoughts and feelings as temporary, objective events in the mind-and whether these gains moderated the relationship between mood-linked cognitive reactivity and relapse of major depression. Findings revealed that CBT responders exhibited significantly greater gains in decentering compared with ADM responders. In addition, high post acute treatment levels of decentering and low cognitive reactivity were associated with the lowest rates of relapse in the 18-month follow-up period. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Paroxetine. A review of its pharmacology, therapeutic use in depression and therapeutic potential in diabetic neuropathy

Paroxetine is a selective serotonin reuptake inhibitor effective in a once-daily administration regimen in the treatment of depression. In elderly patients (aged > or = 60 years) with major depression, short term (6 weeks) treatment with paroxetine produces clinical improvements significantly superior to those seen with placebo and similar to those with tricyclic antidepressant agents, mianserin and fluoxetine. There is evidence that paroxetine has positive effects on co-existing anxiety and does not precipitate agitation. Paroxetine has also shown potential in the symptomatic treatment of diabetic neuropathy; however, further clinical experience is needed to confirm this preliminary result. Short term paroxetine therapy is associated with fewer anticholinergic and CNS adverse effects, but generally more gastrointestinal disturbances, than tricyclic antidepressants and mianserin. Unlike the tricyclic agents, paroxetine does not significantly affect cardiovascular function or impair psychomotor performance. This tolerability profile should be particularly beneficial in elderly patients, who are generally more susceptible than younger patients to the anticholinergic and CNS adverse events associated with tricyclic antidepressant drugs, and in whom there is a higher prevalence of pre-existing cardiovascular disease. It also suggests an important potential advantage over tricyclic antidepressants in the setting of overdosage. Thus, primarily because of its better tolerability profile and potentially lower toxicity in overdosage and in patients with cardiovascular disease, paroxetine appears to be a more attractive option than tricyclic antidepressants for the treatment of depression in late life. Future research should attempt to define more fully the efficacy of paroxetine as long term prophylactic therapy for recurrent depression and to assess how its overall therapeutic profile compares with other selective serotonin reuptake inhibitors in the elderly.     

Personality, stressful life events, and treatment response in major depression.

The current study examined whether the personality traits of self-criticism or dependency moderated the effect of stressful life events on treatment response. Depressed outpatients (N = 113) were randomized to 16 weeks of cognitive–behavioral therapy, interpersonal psychotherapy, or antidepressant medication (ADM). Stressful life events were assessed with the Bedford College Life Events and Difficulties Schedule. Severe events reported during or immediately prior to treatment predicted poor response in the ADM condition but not in the psychotherapy conditions. In contrast, nonsevere life events experienced prior to onset predicted superior response to treatment. Further, self-criticism moderated the relation of severe life events to outcome across conditions, such that in the presence of severe stress those high in self-criticism were less likely to respond to treatment than were those low in self-criticism. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comorbidity of substance dependence and depression: Role of life stress and self-efficacy in sustaining abstinence.

The authors examined life stress and self-efficacy as predictors of time to relapse for 113 adults with comorbid major depressive disorder and alcohol and/or substance dependence in a randomized clinical trial comparing 2 psychotherapy interventions (integrated cognitive- behavioral therapy and 12-step facilitation therapy). Life stress, self-efficacy, and substance use were assessed at treatment entry, 12 weeks (mid-treatment), and 24 weeks (end of treatment). Time to relapse was defined as the number of days from treatment initiation until first alcohol and/or drug use. Half of the sample relapsed within the study period of 24 weeks. There was no significant difference between treatment groups. Individuals experiencing life stressors were more likely to relapse early than those not experiencing life stressors. Lower self-efficacy also predicted earlier relapse. Chronic stress levels and self-efficacy were stable across time for most individuals. In contrast, acute stress events occurred at differing times, and survival analyses provided evidence of heightened relapse risk in the month following acute stressors. The interaction of self-efficacy and life stress was not significant. The results highlight the significance of life stress and self-efficacy as predictors of early relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Fluoxetine

Fluoxetine was developed as an antidepressant drug. It is more effective than placebo, but a dose-effect relation has not been established. Fluoxetine is almost as effective as tricyclic antidepressant drugs, but the available studies do not allow accurate comparisons. Fluoxetine may be less effective than tricyclic antidepressant drugs for the treatment of inpatients with severe melancholic depression, and it should not be the first choice of a drug for them. Fluoxetine may be most appropriate for patients with moderate depression who can be treated as outpatients. If there is little improvement after treatment for four to six weeks, an alternative treatment should be offered. Fluoxetine does not have the anticholinergic, hypotensive, and sedative effects of tricyclic antidepressant drugs and has no particular cardiovascular effects; overdoses do not cause serious toxic effects. Nausea, anorexia, insomnia, and nervousness--the most common side effects--may be controlled with a careful adjustment to the dose. Clinically important drug interactions may occur with monoamine oxidase inhibitors, tricyclic antidepressant drugs, and other drugs. The published data on the antidepressant effect of fluoxetine do not fully explain its popularity. One may speculate that fluoxetine has psychobiologic effects not strictly related to the biology of depression and that it acts primarily as a mood- or affect-modulating agent.     

Milnacipran. A review of its use in depression

Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.     

A depressive syndrome responsive to lithium. An analysis of 20 cases

The authors analyze a series of 20 patients seen over the past 4 years who have shown a dramatic improvement following the introduction of lithium carbonate to their therapy. The results indicate that these patients showed a consistent syndrome with the following features: a) anergic endogenous depression; b) positive family history in first degree probands; c) obsessional personality traits and symptoms; d) hypochondriasis and somatic symptoms; e) failure to respond to previous antidepressant therapy with tricyclic and MAOI compounds as well as ECT. A previous study by Gittleson showed that one third of a series of psychotic depressives admitted to the Maudsley Hospital, London, also displayed obsessional symptoms and hypochondriasis. These patients, however, seemed to do as well with standard antidepressant treatment as a control group of psychotic depressives without obsessional features. However, in this series, there was a 7 per cent residue whose obsessional symptoms worsened, even after recovery from their depression. The authors' group of patients represented approximately 3 per cent of all psychotic depressives seen over the 4-year period and could, therefore, coincide with Gittleson's residue. The mean age of onset of illness in the authors' depressive group was 45.5 years, and this finding, coupled with the high incidence of psychotic depression in first degree relatives, indicates that these patients were suffering from a psychotic depression modified by personality traits, rather than an atypical obsessional neurosis. The consistency of clinical features and specificity of response to lithium therapy appear to indicate that this is a clearly definable clinical syndrome worthy of further investigation.     

Reliability of diagnostic tests for contact allergy to mydriatic eyedrops

AIM: To perform a clinical trial of selegiline in 25 patients with chronic fatigue syndrome (CFS) where patients were told they would receive placebo or active agent at different times during the 6-week trial. We chose selegiline, a specific monoamine oxidase (MAO) B receptor inhibitor, because a prior trial of lowdose phenelzine, a nonspecific MAO inhibitor, showed a small but significant therapeutic effect. METHODS: Questionnaires comprised of 19 tests of mood, fatigue, functional status and symptom severity were collected at the start and end of the trial as well as 2 weeks after its start. The trial was done in three 2-week blocks: in the first, 2 placebo pills were given per day; in the next, one 5-mg tablet of agent and one placebo were given per day, and in the last, a 5-mg tablet of agent was given twice a day. The plan was to compare the changes in the 19 tests during the placebo phase to those found in the active treatment phase in 19 patients completing the trial. FINDINGS: Significant improvement in 3 variables-tension/anxiety, vigor and sexual relations-was found. A significant pattern of improvement compared to worsening was found for the 19 self-report vehicles during active treatment as compared with placebo treatment. Evidence for an antidepressant effect of the drug was not found. CONCLUSIONS: Selegiline has a small but significant therapeutic effect in CFS which appears independent of an antidepressant effect.