Refractory Mood Disorders Research Articles

A Novel Refractory Mood Disorders and Electroconvulsive Therapy Elective for Medical Students: Fighting Stigma through Experience.

Treatment resistant mood disorders (TRMD) have a significant impact on patients and society. Electroconvulsive therapy (ECT) has been shown to be effective for treatment resistant depression (TRD). Despite the effectiveness and safety of ECT, there remains significant stigma surrounding its use. Studies worldwide have shown that many medical students receive their knowledge from the media, which often portrays ECT in a negative light, and very few have exposure to ECT prior to their psychiatric clinical rotations. In this article we highlight the importance of medical education and introduce a novel approach in helping to fight the stigma of ECT through educational intervention for medical trainees that combines active, longitudinal and theoretical learning. By ensuring that trainees have a robust education in this arena, we can help them educate patients about treatment options, improve confidence in prescribing and administering these therapies, and ultimately improve patient and societal outcomes.

Electroconvulsive Therapy as a Treatment for Tardive Dyskinesia.

To review the published literature over the last 10 years for the use of electroconvulsive therapy (ECT) in tardive dyskinesia (TD), focusing on the efficacy of this treatment. A comprehensive evidence search of the published literature in the last 10 years (2010-2020) was conducted using the search terms electroconvulsive therapy, electroshock therapy, ECT, tardive dyskinesia, and tardive dystonia. The review was limited to articles published in the English language. MEDLINE, Embase, PubMed, PsycInfo, Cochrane Library, Google Scholar, and the NICE (National Institute for Health and Care Excellence) guidelines were also searched. Twenty-three case studies published within the last 10 years were retrieved. The search revealed 5 articles of potential relevance. The articles were analyzed by both authors to obtain clinical information relevant to meeting the objectives of the review. The efficacy in using ECT for TD is derived only from case series and case reports. There were no controlled trials, and the evidence collated was limited and of low quality. The review indicates that ECT could be considered as a treatment for TD. However, this treatment may only be considered when patients present with a coexistent refractory mood or affective disorder. Further clinical trials are needed to improve understanding regarding the efficacy, tolerability, and safety of using ECT in this patient group.

Electroconvulsive Therapy for the Treatment of Severe Mood Disorders During Adolescence: A Retrospective Chart Review.

Objective: Electroconvulsive therapy (ECT) is a well-recognized treatment of refractory mood disorders in adults. However, relatively little is known about its use for similar conditions in adolescents. Based on a chart review, we describe its use and outcome in a sample of adolescents with severe, refractory mood disorders (unipolar or bipolar disorder) hospitalized in an academic medical center. Methods: The sample was drawn from referrals to an adolescent psychiatry service. After obtaining approval from the ethics board, medical records of 54 adolescents with refractory mood disorder were examined. Participants (males 24, females 30; mean age 15.8 ± 1.5 years) had received their first course of ECT before the age of 18 years during the period 1996-2010. Response to treatment was examined after the initial treatment and during a 1-year follow-up. Results: Following the index course of ECT (mean number of treatments = 13.7 ± 6.3), a 52.8% response rate (defined as a Clinical Global Impressions [CGI] score ≤2) was noted, while 15.1% achieved remission (CGI = 1). The response rate was 82.4% after a 1-year follow-up with a remission rate of 23.5%. The Children's Depression Rating scores declined significantly from pre-ECT to the end of the index course (70.7 ± 16.4 to 52.5 ± 18; p ≤ 0.00). A reduction in suicidal ideation and self-injurious behaviors along with increased school attendance was noted. Cognition, monitored by the Mini-Mental State Examination, did not decline significantly. Minor side effects were limited to the day of the treatment. Prolonged seizures (>2 minutes) were common during ECT (74% of subjects experienced one or more). The only side effect noted at the 1-year follow-up was self-reported memory loss involving events during and around the index treatment course. Conclusions: In this severely impaired sample of adolescents, ECT was found to decrease suicidal behavior, reduce depressive symptoms, and improve overall functioning, as indexed by school attendance at follow-up after 1 year. Prospective studies using large samples are needed to determine its effectiveness and safety in refractory mood disorders in adolescents.

La thérapie cognitivo-comportementale dans les cliniques spécialisées du Pavillon Albert-Prévost dans les 50 dernières années : innovations et évolution

Le Pavillon Albert-Prévost (PAP) a joué un rôle de premier plan dans le développement d’une psychiatrie moderne. Cette institution de soins et d’enseignement en santé mentale a été profondément marquée par la pensée freudienne et a longtemps été considérée comme un lieu phare de l’enseignement de la psychanalyse en milieu hospitalier au Québec. Mais le PAP a aussi su intégrer au fil des ans d’autres approches thérapeutiques, basées sur les données probantes. Si l’arrivée de cliniciens novateurs dans les années 1980, a permis la sensibilisation du milieu à d’autres approches thérapeutiques, la transformation du dispositif de soins en cliniques spécialisées, en 1994, marque un point décisif dans le développement de la thérapie cognitivo-comportementale, mais surtout dans son intégration dans le traitement quotidien de patients souffrant de problématiques diverses et dans son enseignement à des générations de cliniciens.

Direct Electrical Stimulation of Lateral Orbitofrontal Cortex Acutely Improves Mood in Individuals with Symptoms of Depression

Mood disorders cause significant morbidity and mortality, and existing therapies fail 20%-30% of patients. Deep brain stimulation (DBS) is an emerging treatment for refractory mood disorders, but its success depends critically on target selection. DBS focused on known targets within mood-related frontostriatal and limbic circuits has been variably efficacious. Here, we examine the effects of stimulation in orbitofrontal cortex (OFC), a key hub for mood-related circuitry that has not been well characterized as a stimulation target. We studied 25 subjects with epilepsy who were implanted with intracranial electrodes for seizure localization. Baseline depression traits ranged from mild to severe. We serially assayed mood state over several days using a validated questionnaire. Continuous electrocorticography enabled investigation of neurophysiological correlates of mood-state changes. We used implanted electrodes to stimulate OFC and other brain regions while collecting verbal mood reports and questionnaire scores. We found that unilateral stimulation of the lateral OFC produced acute, dose-dependent mood-state improvement in subjects with moderate-to-severe baseline depression. Stimulation suppressed low-frequency power in OFC, mirroring neurophysiological features that were associated with positive mood states during natural mood fluctuation. Stimulation potentiated single-pulse-evoked responses in OFC and modulated activity within distributed structures implicated in mood regulation. Behavioral responses to stimulation did not include hypomania and indicated an acute restoration to non-depressed mood state. Together, these findings indicate that lateral OFC stimulation broadly modulates mood-related circuitry to improve mood state in depressed patients, revealing lateral OFC as a promising new target for therapeutic brain stimulation in mood disorders.

Long-term treatment with supraphysiologic doses of levothyroxine in treatment-refractory mood disorders – A prospective study of cardiovascular tolerability

BackgroundTo investigate long-term effects of adjunctive prophylactic treatment with supraphysiologic doses of levothyroxine (L-T4) on cardiovascular tolerability in 23 patients with treatment-refractory mood disorders. MethodsStarting point for a comprehensive cardiovascular assessment in patients was the indication for long-term maintenance treatment with L-T4 (mean dose 463 mcg/day). Prospective longitudinal assessment of the cardiovascular risk profile included in addition to a physical examination and blood pressure measurement, several technical investigations: resting electrocardiogram, transthoracic echocardiogram, cardiac stress test, and holter electrocardiogram. Statistical analysis was performed by linear mixed effects models (LMM) for evaluation of longitudinal changes in various heart measures. ResultsDuring the mean observational period of 20.4 months none of the heart measures reached statistical significance in change over time. None of the assessed cardiac parameters of each single patient was in a range predictive for cardiac dysfunction. LimitationsSmall sample size, no technical cardiac investigations prior to L-T4 initiation, no patient control group with mood disorders who did not receive L-T4. ConclusionsResults of this study indicated no increased risk for cardiovascular disorders during treatment with supraphysiologic L-T4 doses in patients with refractory mood disorders.

Neuromodulation Is Gaining Momentum

This issue of Psychiatric Annals, guest edited by Dr. Khurshid A. Khurshid, focuses on which neuromodulation models can be used effectively to treat an array of mental disorders. As defined in this issue, the techniques used to administer some of the newer neuromodulation treatments are less invasive, which may increase patient satisfaction and remission. The first article, “Overview of the Current Use of Deep Brain Stimulation in Psychiatric Disorders,” by Drs. Daniel P. Witter and Herbert E. Ward reviews the history of deep brain stimulation, which started as a treatment for refractory mood disorders. The second article, “Update on Transcranial Magnetic Stimulation for Depression and Other Neuropsychiatric Illnesses,” by Drs. Jonathan E. Becker, Christopher Maley, Elizabeth Shultz, and Warren D. Taylor overviews transcranial magnetic stimulation and its use in clinical practice for the treatment of depression and other disorders. Next, transcranial direct current stimulation (tDCS) is discussed by Sarah M. Szymkowicz, Molly E. McLaren, and Drs. Uma Suryadevara and Adam J. Woods in the article “Transcranial Direct Current Stimulation Use in the Treatment of Neuropsychiatric Disorders: A Brief Review.” The authors review the efficacy of tDCS in depression, while proposing that more in-depth studies are warranted to understand the benefits of this treatment model, as well as other neuromodulation techniques that seek to alleviate the symptoms of psychiatric disorders. The final article, “Charting the Course of Electroconvulsive Therapy: Where Have We Been and Where Are We Headed?,” by Drs. Peter B. Rosenquist, W. Vaughn McCall, and Nagy Youssef details electroconvulsive therapy (ECT) and what methods are used to select patients who are a best fit for this treatment modality. A recent finding suggests that the medication pramipexole may be an alternative when ECT fails for patients with treatment-refractory depression.1 Although neuromodulation systems are emerging in the psychiatry field, there’s still lots of work necessary to balance medication-based therapies with psychotherapeutic methods; the long-term goal is the implementation of more effective holistic treatment modalities for all patients regardless of their disorder.

A hypothesis on the mechanism of action of high-dose thyroid in refractory mood disorders

Multiple lines of evidence suggest the hypothesis that high dose thyroid therapy corrects for cellular hypothyroidism found in bipolar disorders. Evidence indicates that bipolar disorders are associated with mitochondrial dysfunction which results in low cellular adenosine 5′-triphosphate (ATP) levels. Transport of thyroid hormones into cells is energy intensive and dependent on ATP except in the pituitary gland. Inadequate ATP levels makes it difficult to get thyroid hormone into cells leading to cellular hypothyroidism. This creates a condition where the blood and pituitary levels of thyroid hormone are normal but low in other tissues. High dose thyroid therapy produces a gradient that is sufficient for thyroid hormone to diffuse into cells correcting cellular hypothyroidism. If this hypothesis is correct there are number of implications. The two most important are: On average patients suffering from a bipolar disorder die 10–20years earlier than the general population. The medical sequelae associated with bipolar disorders cause far more deaths than suicide. If high dose thyroid corrects for cellular hypothyroidism it could well decrease the medical morbidity and mortality associated with bipolar disorders that are the result of cellular hypothyroidism. Thus high dose thyroid would be a first treatment that decreases the considerable medical morbidity and mortality associated with the bipolar disorders. This would stand in stark contrast to most psychiatric medications that can that increase morbidity and mortality. It would also reinforce the safety of HDT. The second implication is thyroid hormone blood levels in patients suffering from a bipolar disorder do not accurately reflect the true thyroid status.

A New Perspective on the Anti-Suicide Effects With Ketamine Treatment: A Procognitive Effect.

Available evidence indicates that a single, low-dose administration of ketamine is a robust, rapid-onset intervention capable of mitigating depressive symptoms in adults with treatment-resistant mood disorders. Additional evidence also suggests that ketamine may offer antisuicide effects. Herein, we propose that the antidepressant effects reported with ketamine administration are mediated, in part, by targeting neural circuits that subserve cognitive processing relevant to executive function and cognitive emotional processing. Empirical support for the conceptual framework of the cognitive domain as a critical target of ketamine's action is the additional observation that pretreatment cognitive function predicts treatment outcomes with ketamine administration. The proposal that beneficial effects on cognitive function may be, in some individuals, the proximate mechanism mitigating symptom relief in mood disorders exists alongside the well-established deleterious effect of ketamine on cognitive function. During the past 5 years, there have been several reviews and meta-analyses concluding that ketamine has possible clinical benefits in refractory mood disorders. We introduce the conceptual framework that ketamine's salutary effects, notably in suicidality, may in part be via procognitive mechanisms.

Treatment-resistant mood disorders

Treatment-resistant mood disorders

The promise of cognitive behavior therapy for treatment of severe mental disorders: a review of recent developments.

Cognitive behavior therapy (CBT), as exemplified by the model of psychotherapy developed and refined over the past 40 years by A.T. Beck and colleagues, is one of the treatments of first choice for ambulatory depressive and anxiety disorders. Over the past several decades, there have been vigorous efforts to adapt CBT for treatment of more severe mental disorders, including schizophrenia and the more chronic and/or treatment refractory mood disorders. These efforts have primarily studied CBT as an adjunctive therapy, i.e., in combination with pharmacotherapy. Given the several limitations of state-of-the-art pharmacotherapies for these severe mental disorders, demonstration of clinically meaningful additive effects for CBT would have important implications for improving public health. This paper reviews the key developments in this important area of therapeutics, providing a summary of the current state of the art and suggesting directions for future research.

Treatment refractory mood disorders: Case report

CASE BF is a 42 year-old Caucasian male who reported his onset of depression began four years ago after he was involved in a car accident that fractured his hip. He was not treated for depression until he overdosed on approximately 50 aspirin 325 mg tablets and 750 ml of whiskey (seven months following the accident). After being medically cleared from the emergency room and acute inpatient unit, he was transferred to inpatient psychiatry for evaluation of depression. Upon admission to the inpatient psychiatric unit, his labs were found to be within normal limits (WNL) except a slight elevation in gamma-glutamyl transferace (GGT) at 51 U/L, likely from his acute alcohol ingestion. His thyroid panel was also WNL. He denied any other illness or taking any other medications.

Aripiprazole in the treatment of refractory mood disorders: a case series.

Major depressive disorder and bipolar disorders are among the commonest neuropsychiatric conditions, affecting persons of both sexes which belong to all age groups. Comorbidity is the rule rather than the exception; anxiety spectrum disorders, somatoform disorders, eating disorders and substance use disorders frequently co-exist with mood disorders. Catatonia is a serious complication of the latter and every patient with a severe affective exacerbation should be assessed for the presence of catatonic signs and symptoms. In a significant minority of patients, symptoms show treatment resistance; many patients experience severe hopelessness and suicidal ideation, causing high rates of morbidity and mortality in afflicted individuals. Pharmacological management is challenging and currently available psychotropic agents often fall short of inducing remission. Second generation antipsychotics have been shown in a number of studies as having an antidepressant and mood stabilizing effect. Aripiprazole is a novel antipsychotic which is being increasingly used in difficult to treat mood disorders patients. Several controlled and uncontrolled studies have shown the efficacy and safety of this medication in subjects of all ages. Here a case series of three patients is presented who suffered from refractory mood disorders but responded to aripiprazole with complete remission of affective symptoms.

Ketamine as a Fast Acting Antidepressant: Current Knowledge and Open Questions

Several recent studies have shown that a single intravenous subanesthetic dose of ketamine, a NMDA receptor antagonist, exerts rapid antidepressant effects in patients with treatment refractory mood disorders and reduces suicidal ideation. Those insights have fueled tremendous excitement in the efforts to elucidate the mechanism underlying ketamine's antidepressant properties in animal models of depression, as well as in humans through the use of brain imaging as well as peripheral blood measurements. For example, there is emerging evidence that ketamine's antidepressant properties rely on increasing AMPA signaling and rapidly inducing synaptogenesis. While pilot clinical studies are promising, a number of critical questions still remain unanswered. They relate to the safe and effective use of ketamine in patients with mood disorders regarding the optimal dose range, modality and method of administration for acute and long-term maintenance of effect, and the biomarkers associated with response/nonresponse. In this review article, we first summarize the clinical evidence about the use of ketamine in mood disorders, as well as preclinical and humans studies which investigated the mechanisms of action of ketamine, and predictors of antidepressant response in clinical populations. We then provide a critical overview of the knowledge gaps about the use of ketamine in depression and suggest some future research directions for the investigation of ketamine as a promising tool to develop novel more effective and fast acting antidepressants.

Maintenance Treatment of Bipolar Disorder with Ziprasidone in Adjunctive Use with Lithium or Valproate

Ziprasidone is a second generation (“atypical”) antipsychotic drug that has been used alone and as an adjunct to standard mood stabilizers to reduce recurrence rates in bipolar disorder. Approval of ziprasidone as an adjunct to lithium or valproate in 2009 was based on an industry sponsored study of 584 outpatients with a current or recent manic episode; 240 of these subjects were randomized to adjunctive ziprasidone or placebo and 138 completed a six month trial. Patients enrolled in maintenance studies did not have refractory mood disorders, comorbid conditions or risk of dangerousness. Maintenance ziprasidone augmentation is an option for patients who do not respond to a single mood stabilizer rapidly, and possibly for those with residual psychotic symptoms, but there are insufficient data to prefer this approach to combinations of mood stabilizers or augmentation with other agents. Ziprasidone is generally well tolerated, with less sedation and weight gain than many other antipsychotic drugs; it should be taken with food. Primary interactions of concern are with other serotonergic medications, MAO inhibitors, and other medications that prolong the QT interval.

Ziprasidone for maintenance treatment of bipolar I disorder in adults

Introduction: Antipsychotic drugs are increasingly used in the maintenance treatment of bipolar disorder. This review addresses the evidence supporting the use of one of these medications for this indication in order to place available data in perspective for the clinician.Areas covered: The approval of ziprasidone for maintenance treatment of bipolar I disorder was based on two open-label extensions of industry-sponsored 3-week monotherapy trials in mania, involving a total of 189 patients and an industry-sponsored study using sample enrichment of 584 outpatients who had either ziprasidone or a placebo added to lithium or valproate. Patients enrolled in maintenance studies did not have refractory mood disorders or comorbid conditions or risk of dangerousness, and they were able to give sustained consent. Ziprasidone is generally well tolerated, but should be taken with food. Primary interactions of concern are those with other serotonergic medications and other medications that prolong the QT interval.Expert opinion: Although antipsychotic drugs are used frequently for maintenance treatment, current guidelines recommend that an attempt be made to withdraw them after acute treatment. The use of these medications as part of a maintenance regimen is most appropriate in cases of persistent psychosis or failure to respond to standard mood stabilizer combinations.

Transtornos de humor refratários a tratamento

Mood disorders are the most prevalent psychiatric disorders. Despite new insights and advances on the neurobiological basis and therapeutic approaches for bipolar disorders and recurrent depression, elevated prevalence of recurrence, persistent sub-syndromal symptoms and treatment resistance are challenging aspects and need to be urgently addressed. The objective of this literature review is to evaluate the current concepts of treatment resistance and refractoriness in mood disorders. Genetic factors, misdiagnosis, use of inappropriate pharmacological approaches, non-compliance and biological/psychosocial stressors account for dysfunctions in mood regulation, thus increasing the prevalence of refractory mood disorders. Regarding available treatments, the use of effective doses during an adequate period followed by augmentation with a second and/or third agent, and finally switching to other agent are steps frequently necessary to optimize efficacy. However, in the treatment-resistant paradigm, drugs mimicking standard strategies, which target preferentially the monoaminergic system, can present reduced therapeutic effects. Thus, the search for new effective treatments for mood disorders is critical to decreasing the overall morbidity secondary to treatment resistance. Emerging strategies targeting brain plasticity pathways or 'plasticity enhancers', including antiglutamatergic drugs, glucocorticoid receptor antagonists and neuropeptides, have been considered promising therapeutic options for difficult-to-treat mood disorders.

Deep brain stimulation for treatment-resistant depression: A psychiatric perspective

Traditionally, the therapeutic approach to treatment-resistant depression (TRD) has relied on pharmacotherapy in various sequences and combinations, in addition to evidence-based psychotherapy or electroconvulsive therapy. Despite refinements to the existing therapeutic modalities, there remains a significant subpopulation of severely ill patients with refractory mood disorders who fail to achieve a clinical response despite aggressive psychosocial and biological treatments. Interest in the use of deep brain stimulation (DBS) for treatment-resistant psychiatric illness has emerged in recent years for a number of reasons: 1) as part of a general re-evaluation of both noninvasive and invasive brain stimulation techniques, 2) because of the demonstrated clinical efficacy of DBS for movement disorders, and 3) as a logical consequence of studies defining the functional neurocircuitry of several psychiatric disorders. This review will examine the progress of DBS in the treatment of Parkinson's disease and the potential implications for its use in TRD, as well as the role of the psychiatrist in selection and ongoing management of patients who receive this procedure.

Aripiprazole Augmentation in Treatment-Resistant Depression

Evidence is accumulating to support the use of atypical neuroleptics as adjunctive treatment for refractory mood disorders, although there are currently no published data on the efficacy of an atypical neuroleptic in treatment-resistant depression when a previous trial of drug from the same class has failed. The authors hypothesized that aripiprazole would be efficacious in augmenting antidepressant treatment in resistant patients with non-psychotic unipolar depression who had previously failed a trial of another atypical neuroleptic. This study was a retrospective chart review of the efficacy of aripiprazole augmentation in 30 treatment-resistant unipolar depression patients who had failed multiple previous antidepressant trials and had also failed augmentation with at least one other atypical neuroleptic. Prospective Global Assessment of Functioning and Clinical Global Impressions-Improvement scores were completed on each patient throughout treatment. Utilizing an intent-to-treat analysis (including 9 patients who dropped out prior to completion of 6 weeks), 46.7% (14/30) patients were rated much improved or very much improved with treatment. This improvement negatively correlated with Thase-Rush staging of treatment resistance. GAF scores also showed a significant improvement. Six of the 14 patients who initially improved subsequently relapsed (yielding a long-term net response rate of 26.7%). Aripiprazole may be effective as an antidepressant augmentation agent in highly treatment resistant patients who had failed a prior trial of another atypical neuroleptic.

At Annual Meeting, Why Not Try Case Conferences?

Back to table of contents Previous article Next article Annual MeetingFull AccessAt Annual Meeting, Why Not Try Case Conferences?Catherine Crone, M.D.Catherine CroneSearch for more papers by this author, M.D.Published Online:2 Apr 2004https://doi.org/10.1176/pn.39.7.0063aWhile much of APA’s annual meeting is devoted to continuing education through lectures, poster sessions, and industry-sponsored symposia, there are other venues that APA members may be less familiar with but are equally informative. These venues include the clinical case conferences and continuous case conferences, both of which allow APA members to expand their knowledge in a more intimate and interactive setting.The format for both types of conferences involves the presentation of selected case material followed by discussion of a specific topic relevant to each case. All case conferences are a blend of formal presentation and interactive dialogue with the audience, who are provided ample time for questions and dialogue with invited speakers and discussants.Over the years, case conferences have covered a broad range of topics, including diagnosis and management of adolescents with ADHD and bipolar disorder, motivational enhancement therapy for addicted patients, affect dysregulation, and new perspectives on transference. This year’s case conferences will address the challenges of providing psychiatric care to the cardiovascular patient and the HIV patient, as well as difficult physician-patient boundary issues in somatization disorder.Continuous case conferences provide an opportunity for APA members to explore chosen cases and topics in even greater detail. Because they occur over two days, continuous cases can progress from diagnosis through much of the treatment course and focus on more complex therapeutic issues. This year’s presentations include therapeutic approaches to counter demoralization and assessment of patients with refractory mood and cognitive disorders; the latter session involves faculty from Baylor College of Medicine and the Menninger Clinic.APA members interested in presenting future clinical case and continuous case conferences are encouraged to contact me at APA, Annual Meetings Office, 1000 Wilson Boulevard, Arlington, Va. 22209. ▪Catherine Crone, M.D., is a member of APA’s Scientific Program Committee and chair of the case conference formats. ISSUES NewArchived