Alternative approaches to refractory depression in bipolar illness

This article is a U.S. government work, and, as such, is in the public domain in the United States of America.     

New approaches to managing psychotic depression

Major depression with psychotic features, while fairly common, is frequently misdiagnosed. Symptoms seen in these patients are those of an overall severe depressive disorder with psychomotor impairment (retardation or agitation), guilt, suicidal preoccupation, and neuropsychological impairment. A number of biological characteristics and behavioral symptoms are specific to patients suffering from psychotic depression and differ significantly from those of nonpsychotic depression. Psychotic depression is seen in patients of all ages, and it has a high short-term morbidity and risk of suicide. Data support the use of antipsychotics in combination with antidepressants for major depression with psychotic features, but other treatments may have as great or greater efficacy for the disorder. This article focuses on recognizing the features of psychotic depression, the success of current treatment options, and new treatments under investigation.     

Therapeutic approaches to the treatment of refractory obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a debilitating condition that afflicts approximately 1% to 3% of the world population. The primary treatments are selective serotonin reuptake inhibitors and behavioral therapy. Despite therapy, approximately 30% to 40% of patients continue to suffer from disabling OCD symptoms. This article addresses the range of treatment options for patients with refractory OCD, focusing upon novel strategies and the most recent research.     

Mirtazapine augmentation in the treatment of refractory depression

BACKGROUND: Pharmacotherapeutic strategies that target specific actions at multiple neuronal receptors or cellular components may offer a superior approach for treatment of refractory depression. Mirtazapine is a novel antidepressant which has a mechanism that involves the enhancement of noradrenergic and serotonergic neurotransmission via blockade of alpha2-adrenergic autoreceptors and heteroreceptors without activity at the serotonin transporter. Mirtazapine is thus a compelling candidate for augmentation treatment in patients who fail to achieve adequate response with other antidepressant medications. METHOD: Twenty patients with DSM-IV major depression or dysthmia who had persistent depressive syndromes despite at least 4 weeks of standard antidepressant pharmacotherapy were given augmentation with mirtazapine (15 to 30 mg p.o. q.h.s.) on an open-label basis. Clinical assessments of status at baseline, 2 weeks, and 4 weeks were used to rate response. RESULTS: Forty-five percent (N = 9) of the sample were responders at 2 weeks. At the 4 week follow-up, 55% (N = 11) were responders, 30% (N = 6) were nonresponders, and 15% (N = 3) had discontinued treatment owing to side effects. Common side effects included weight gain and sedation. CONCLUSION: These data suggest that the addition of mirtazapine may be beneficial for patients who have refractory depression, but side effects are prominent at the doses we used. Controlled trials to further evaluate the efficacy and safety of mirtazapine augmentation are needed.     

Novel treatment approaches for refractory anxiety disorders

The Anxiety Disorders Association of America convened a conference of experts to address treatment-resistant anxiety disorders and review promising novel approaches to the treatment of refractory anxiety disorders. Workgroup leaders and other participants reviewed the literature and considered the presentations and discussions from the conference. Authors placed the emerging literature on new therapeutic approaches into clinical perspective and identified unmet needs and priority areas for future research. There is a relative paucity of efforts addressing inadequate response to anxiety disorder treatment. Systematic efforts to exhaust all therapeutic options and overcome barriers to effective treatment delivery are needed before patients can be considered treatment refractory. Cognitive behavioral therapy, especially in combination with pharmacotherapy, must be tailored to accommodate the effects of clinical context on treatment response. The literature on pharmacologic treatment of refractory anxiety disorders is small but growing and includes studies of augmentation strategies and non-traditional anxiolytics. Research efforts to discover new pharmacologic targets are focusing on neuronal systems that mediate responses to stress and fear. A number of clinical and basic science studies were proposed that would advance the research agenda and improve treatment of patients with anxiety disorders. Significant advances have been made in the development of psychotherapeutic and pharmacologic treatments for anxiety disorders. Unfortunately, many patients remain symptomatic and functionally impaired. Progress in the development of new treatments has great promise, but will only succeed through a concerted research effort that systematically evaluates potential areas of importance and properly uses scarce resources.     

New approaches in managing bipolar depression

Historically, the pharmacologic treatment of bipolar depression has not been well studied. New data are beginning to emerge regarding the efficacy of new medications and the use of combinations of mood stabilizers and antidepressants in acute and long-term treatment of bipolar depression. We reviewed data from recent randomized, controlled trials of mood stabilizers and antidepressants in the treatment of bipolar depression and naturalistic studies examining the risk of switching and depressive relapse with ongoing antidepressant treatment.     

Efficacy of lithium-tranylcypromine treatment in refractory depression

Twelve inpatients with major depression refractory to at least two controlled antidepressant trials had tranylcypromine added to ongoing lithium treatment. Eleven patients showed reliable improvement in nurses' depression ratings compared with a prior trial of lithium added to an antidepressant that was not a monoamine oxidase inhibitor (MAOI). Eight patients were blindly judged much or very much improved, and all 12 patients improved sufficiently to be discharged. Preclinical studies of conjointly administered lithium and MAOIs suggest that central serotonergic pathways may mediate this robust clinical effect.     

Lithium augmentation in psychotic depression refractory to combined drug treatment

In this retrospective study the authors determined the efficacy of lithium added to a combined antipsychotic-antidepressant drug regimen in 21 psychotically depressed patients who had been refractory to combined drug treatment. Response to lithium was then compared with response rates of 15 patients to ECT, the established treatment for nonresponsive delusional depression. Lithium was effective in eight of nine patients with bipolar depression but in only three of 12 patients with unipolar depression; ECT was effective in nine of 15 patients with unipolar depression. Lithium augmentation appeared to be a realistic treatment alternative for refractory bipolar patients but was disappointing in unipolar patients.     

Addition of lithium to thymoleptic drugs in the treatment of therapy refractory depression

The paper gives a short overview of the open and controlled investigations which have been published on the subject. The therapeutic efficacy of lithium addition is now quite well documented, and its use may be recommended in depressions refractory to conventional thymoleptic drug treatment. Preliminary conclusions with regard to the practical use of lithium addition are made.     

Stem cell therapy: a new approach to the treatment of refractory depression

To better understand the relationship of repeated exposure to adversity during early development as a risk factor for refractory depression, we exposed pregnant female rats to ethanol and the resulting pups to corticosterone during adolescence. A stressful forced swim test was then used to induce depression-like behavior. The adolescent rat brains were examined for the possible therapeutic benefit of a combination of sertraline, an antidepressant, and neural stem cells (NSCs) complexed with atelocollagen in relation to the level of GABAergic interneuron and synaptic protein density in different brain regions. The combined exposures of prenatal and adolescent stress resulted in a reduction in parvalbumin (PV)-positive phenotype of GABAergic interneurons and reduced postsynaptic density protein 95 (PSD-95) levels in the anterior cingulate cortex, amygdala, and hippocampus. Treatments with sertraline and NSCs reversed the reductions in PV-positive cells and PSD-95 levels. Furthermore, the combined treatment of sertraline and NSCs resulted in reduced depressive-like behaviors. These experiments underscore a potentially important role for synaptic remodeling and GABAergic interneuron genesis in the treatment of refractory depression and highlight the therapeutic potential of stem cell and pharmacological combination treatments for refractory depression.     

New pharmacological approaches to the management of depression: from theory to clinical practice.

A review of the clinical efficacy of four structurally distinct antidepressant drugs is presented. Their antidepressant activity can be rationalised within current pharmacological hypotheses of drug action, despite markedly different effects on "in vitro" testing. Fluoxetine, a specific serotonin re-uptake inhibitor, has proven safe, effective treatment for depressive illness and may have a role to play in the treatment of obsessive-compulsive disorder and panic attacks. While it has few of the anticholinergic side effects of the tricyclic antidepressants, nausea, tremor, headache, weight loss, nervousness and sweating are side effects most frequently reported. Minaprine, a compound with weak MAO inhibiting properties and effects on serotonergic receptors, has clinical efficacy in the treatment of depression based on several comparative studies. It is claimed that minaprine lacks anticholinergic and sedative properties. Moclobemide, a specific, reversible inhibitor of MAO-A, has been extensively evaluated in depressive illness. The major advantage of this agent over other irreversible, non-specific MAO inhibitors, is the significant attenuation of the so-called "cheese effect" with doses of tyramine likely to be encountered in foodstuffs. Rolipram, a phosphodiesterase inhibitor, represents a new approach to antidepressant treatment. Limited clinical data suggest that the drug may be an effective antidepressant with few side effects. The place of these agents in therapy is yet to be established.     

Pharmacologic approaches to treatment resistant depression: Evidences and personal experience

AIM: To review evidence supporting pharmacological treatments for treatment-resistant depression (TRD) and to discuss them according to personal clinical experience.METHODS: Original studies, clinical trials, systematic reviews, and meta-analyses addressing pharmacological treatment for TRD in adult patients published from 1990 to 2013 were identified by data base queries (PubMed, Google Scholar e Quertle Searches) using terms: “treatment resistant depression”, “treatment refractory depression”, “partial response depression”, “non responder depression”, “optimization strategy”, “switching strategy”, “combination strategy”, “augmentation strategy”, selective serotonin reuptake inhibitors antidepressants (SSRI), tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors antidepressants, mirtazapine, mianserine, bupropione, monoamine oxidase inhibitor antidepressant (MAOI), lithium, thyroid hormones, second generation antipsychotics (SGA), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, S-adenosil-L-metionine, methylfolat, pindolol, sex steroids, glucocorticoid agents. Other citations of interest were further identified from references reported in the accessed articles. Selected publications were grouped by treatment strategy: (1) switching from an ineffective antidepressant (AD) to a new AD from a similar or different class; (2) combining the current AD regimen with a second AD from a different class; and (3) augmenting the current AD regimen with a second agent not thought to be an antidepressant itself.RESULTS: Switching from a TCA to another TCA provides only a modest advantage (response rate 9%-27%), while switching from a SSRI to another SSRI is more advantageous (response rate up to 75%). Evidence supports the usefulness of switching from SSRI to venlafaxine (5 positive trials out 6), TCA (2 positive trials out 3), and MAOI (2 positive trials out 2) but not from SSRI to bupropione, duloxetine and mirtazapine. Three reviews demonstrated that the benefits of intra- and cross-class switch do not significantly differ. Data on combination strategy are controversial regarding TCA-SSRI combination (positive results in old studies, negative in more recent study) and bupropion-SSRI combination (three open series studies but not three controlled trails support the useful of this combination) and positive regard mirtazapine (or its analogue mianserine) combination with ADs of different classes. As regards the augmentation strategy, available evidences supported the efficacy of TCA augmentation with lithium salts and thyroid hormone (T3), but are conflicting regard the SSRI augmentation with these two drugs (1 positive trial out of 4 for lithium and 3 out of 5 for thyroid hormone). Double-blind controlled studies showed the efficacy of AD augmentation with aripiprazole (5 positive trials out 5), quetiapine (3 positive trials out 3) and, at less extent, of fluoxetine augmentation with olanzapine (3 positive trials out 6), so these drugs received the FDA indication for the acute treatment of TRD. Results on AD augmentation with risperidone are conflicting (2 short term positive trials, 1 short-term and 1 long-term negative trials). Case series and open-label trials showed that AD augmentation with pramipexole or ropinirole, two dopamine agonists, could be an effective treatment for TRD (response rate to pramipexole 48%-74%, to ropinirole 40%-44%) although one recent double-blind placebo-controlled study does not support the superiority of pramipexole over placebo. Evidences do not justify the use of psychostimulants, omega-3 fatty acids, S-adenosil-L-metionine, methylfolate, pindolol, lamotrigine, and sex hormone as AD augmentation for TRD. Combining the available evidences with our experience we suggest treating non-responders to one SSRI bupropion or mirtazapine trial by switching to venlafaxine, and non-responders to one venlafaxine trial by switching to a TCA or, if TCA are not tolerated, combining mirtazapine with SSRI or venlafaxine. In non-responders to two or more ADs (including at least one TCA if tolerated) current AD regimen could be augmented with lithium salts (mainly in patients with bipolar depression or suicidality), SGAs (mostly aripiprazole) or DA-agonists (mostly pramipexole). In patients with severe TRD, i.e., non-responders to combination and augmentation strategies as well as to electroconvulsive therapy if workable, we suggest to try a combination plus augmentation strategy.CONCLUSION: Our study identifies alternative effective treatment strategies for TRD. Further studies are needed to compare the efficacy of different strategies in more homogeneous subpopulations.     

Drug combinations in the treatment of refractory depression: a review

The authors critically review several drug combinations that may be of promise in the management of depressions that do not respond to treatment with a single drug. These include the use of tricyclic antidepressants with monoamine oxidase inhibitors (MAOI's), L-triiodothyronine (T3), methylphenidate, lithium carbonate, L-tryptophan, reserpine, and neuroleptics; MAOI's with lithium and L-tryptophan; and L-tryptophan with allopurinol. The authors stress the need for further double-blind, controlled studies to evaluate the safety and efficacy of these combinations.     

Lithium augmentation in the treatment of refractory depression in old age

A retrospective study of treatment and outcome is described in 59 consecutive referrals to a catchment psychogeriatric service meeting ICD9 criteria for manic depressive illness or depressive neurosis. Of 22 who failed to respond to tricyclic antidepressants, nine (of whom four had also failed to respond to ECT) were treated by lithium augmentation. Systematic comparisons between lithium-treated subjects, tricyclic responders and others failing to respond to tricyclics revealed no significant demographic differences. Lithium augmentation was successful in 6/9 subjects. Two ‘lithium failures’ were treated with tranylcypromine to good effect. At follow-up (median six months, range 3–20 months) 7/9 subjects in the lithium-treated group were well. This was similar to the follow-up status in tricyclic responders and significantly better than outcome in the other tricyclic non-responders. Lithium augmentation appears to be a relatively well-tolerated treatment manoeuvre in refractory depression in old age, with treatment response similar to that reported in younger subjects, and may be of particular use where ECT has failed.     

Actual approaches to post-psychotic depression]

Clinical features of post-psychotic depression in schizophrenia have been described since the beginning of the century. However, international nosographies mention this concept only since the ICD 10 and the DSM IV. In clinical practice, post-psychotic depression is a real challenge. Currently, the exact prevalence remains undetermined and is estimated about 25%, varying from 7 to 70% in the literature. The diagnostic criteria nowadays available will encourage searchers to determine the exact prevalence of post-psychotic depression. This is surely due to difficulties in the diagnostic approach. The clinical picture resembles that of major depression. However, there are confounding factors such as negative symptoms and extrapyramidal symptoms. With regard to psychometrics, two specific rating scales are thought to measure depressive symptoms in schizophrenia: the Calgary Depression Scale (CDS) and the Psychotic Depression Scale (PDS). Nonetheless, the scales are not specific for post-psychotic depression. Prognosis of an acute schizophrenia is linked among other factors with the emergence of a post-psychotic depression that is in turn influences suicidal risk and quality of life. Genetic, therapeutic, psychodynamic and psychological factors have been invoked in the etiopathogenesis of post-psychotic depression. In clinical practice, post-psychotic depression can be successfully treated with antidepressive medication. Some antidepressants have shown their efficacy.