Nonpharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities

Until recently, a review of nonpharmacological, somatic treatments of psychiatric disorders would have included only electroconvulsive therapy (ECT). This situation is now changing very substantially. Although ECT remains the only modality in widespread clinical use, several new techniques are under investigation. Their principal indication in the psychiatric context is the treatment of major depression, but other applications are also being studied. All the novel treatments involve brain stimulation, which is achieved by different technological methods. The treatment closest to the threshold of clinical acceptability is transcranial magnetic stimulation (TMS). Although TMS is safe and relatively easy to administer, its efficacy has still to be definitively established. Other modalities, at various stages of research development, include magnetic seizure therapy (MST), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). We briefly review the development and technical aspects of these treatments, their potential role in the treatment of major depression, adverse effects, and putative mechanism of action. As the only one of these treatment modalities that is in widespread clinical use, more extended consideration is given to ECT Although more than half a century has elapsed since ECT was first introduced, it remains the most effective treatment for major depression, with efficacy in patients refractory to antidepressant drugs and an acceptable safety profile. Although they hold considerable promise, the novel brain stimulation techniques reviewed here will be need to be further developed before they achieve clinical acceptability.     

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

Traditionally, the therapeutic approach to treatmentresistant 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.     

Neurostimulation therapies in depression: a review of new modalities

OBJECTIVE: In response to an increased understanding of the neurobiology of severe psychiatric disorders, new therapeutic modalities are entering clinical practice that involve the direct stimulation of the brain. METHOD: We provide a review of published literature regarding the clinical use of vagus nerve stimulation (VNS) therapy, transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) in psychiatric disorders, with an emphasis on treatment-resistant depression (TRD). RESULTS: Vagus nerve stimulation is approved for use in both the EU and US for TRD. TMS has been approved for TRD in Canada, Australia, New Zealand, the European Union and Israel, but not yet in the United States. DBS remains in the early stages of investigation. CONCLUSION: While additional studies are clearly warranted, treatments that directly stimulate the brain appear to hold great therapeutic promise for severe psychiatric disorders.     

Current perspectives in the management of treatment-resistant depression

Depressive disorders are a leading cause of disability worldwide and greatly impact morbidity, health care utilization, and medical costs. Major depression that does not resolve with adequate antidepressant treatment is termed treatment-resistant depression (TRD), There is no universally accepted definition of TRD and several criteria have been suggested to define it. Multiple factors can contribute to treatment resistance, including unrecognized comorbid medical or psychiatric illness, the use of concomitant medications, noncompliance, and psychosocial stressors. TRD is associated with extensive use of depression-related and general medical services, and poses a substantial economic burden. Current approaches to its management include the use of antidepressant strategies, such as increasing the dose of the antidepressant, augmentation strategies, combination strategies, and switching strategies, electroconvulsive therapy, and cognitive behavioral therapy. Although no definite algorithm exists for treating TRD, research in this area has advanced considerably in recent years. One approach to this is a clinical trial called STAR*D (Sequenced Treatment Alternatives to Relieve Depression). This has the potential to increase our understanding about the diagnostic and therapeutic aspects of TRD, to substantially reduce disability, and to enhance the quality of life in individuals with this condition.     

Electroconvulsive therapy and its different indications

In spite of recent developments in the pharmacotherapy of depressive disorders, the delay until clinical improvement can be achieved, and the considerable rate of nonresponse and nonremission, are major problems which remain unresolved. Electroconvulsive therapy (ECT) is a nonpharmacologic biological treatment which has been proven to be a highly effective treatment option, predominantly for depression, but also for schizophrenia and other indications. Though there is a lack of controlled investigations on long-term treatments, ECT can also be used for relapse prevention during maintenance therapies. The safety and tolerability of electroconvulsive treatment have been enhanced by the use of modified stimulation techniques and by progress in modern anesthesia. Thus, today a safe treatment can also be offered to patients with higher somatic risks. ECT still represents an important option, especially in the therapy of treatment-resistant psychiatric disorders after medication treatment failures. Earlier consideration of ECT may reduce the rate of chronic and difficult-to-treat psychiatric disorders.     

Behavioral and psychiatric consequences of sleep-wake schedule disorders

Circadian rhythm sleep disorders (CRSDs) arise when an individual's sleep-wake rhythm mismatches the environmental 24-h schedule. Physiological data and genetic studies in patients with CRSDs suggest that these disorders result from abnormal functioning of the circadian timing system. Diagnosis involves recognition of the characteristics of CRSDs, which can be achieved by clinical interview and actigraphic monitoring of rest-activity patterns. Bright-light therapy and melatonin administration have proved to be the most effective treatment modalities of CRSDs. In psychiatric practice, CRSDs can be encountered on various occasions. Some evidence indicates that a deviant sleep-wake schedule might be a predisposing factor to personality disorders. CRSDs can emerge as an iatrogenic effect of certain psychoactive drugs, such as haloperidol and fluvoxamine. It is not uncommon that the daytime functional difficulties that accompany CRSDs are misinterpreted as symptoms of psychopathology. Recognition and awareness of these disorders should prevent years of erroneous diagnosis and treatment in these patients.     

ADHD in adolescence and adulthood, with a special focus on the dopamine transporter and nicotine

The persistence of attention deficit hyperactivity disorder (ADHD) into adolescence and adulthood has now been accepted as a clinical entity. The rate of prevalence among adults is assumed to be from 2% to 4%. With increasing age, a symptom change has to be considered; disturbance of attention becomes more prominent, whereas hyperactivity often diminishes or changes to inactivity. Neuroimaging studies show a high striatal dopamine transporter (DAT) availability in most adults with ADHD; this can be reduced by stimulants. Nicotine seems to have a stimulant-like action on the DAT. In most adults with ADHD, therapy has to be multimodal, combining psychotherapy and medication. Methylphenidate is the first-line drug in adult ADHD; further options are amphetamine and noradrenaline reuptake inhibitors. Nonresponders to methylphenidate seem to have no elevated DAT availability prior to therapy. Combination with other psychiatric disorders occurs frequently in adults with ADHD; in these patients additional pharmacological treatment with special regard to the comorbid disease is recommended.     

Incomplete remission in depression: role of psychiatric and somatic comorbidity

Depression is one of the most pressing public health issues, because of its high lifetime prevalence and because it is associated with substantial disability. In depressed patients, psychiatric and medical comorbidity is the rule rather than the exception. About 60% to 70% of depressed patients have at least one, while 30% to 40% have two or more, concurrent psychiatric disorders. Among these, anxiety disorders and substance use disorders are the most common axis I comorbidities. Furthermore, two thirds of depressed patients have at least one comorbid medical illness. Among depressed patients, those with a current comorbid psychiatric condition (in particular an anxiety or substance use disorder) or medical illness seem to have an impaired response and remission rate during treatment compared with those patients without comorbidity. However, in depressed patients who all have the same comorbid condition, the relative benefit of an antidepressant compared with placebo appears to be equal to those effects achieved in depressed patients without comorbidity. These findings raise important research and treatment issues regarding the generalizability from randomized controlled trials that tend to exclude patients with comorbidity.     

Use of proton magnetic resonance spectroscopy in the treatment of psychiatric disorders: a critical update

Because of the wide availability of hardware as well as of standardized analytic quantification tools, proton magnetic resonance spectroscopy (¹H-MRS) has become widely used to study psychiatric disorders. ¹H-MRS allows measurement of brain concentrations of more traditional singlet neurometabolites like N-acetylaspartate, choline, and creatine. More recently, quantification of the more complex multiplet spectra for glutamate, glutamine, inositol, and γ-aminobutyric acid have also been implemented. Here we review applications of ¹H-MRS in terms of informing treatment options in schizophrenia, bipolar disorder, and major depressive disorders. We first discuss recent meta-analytic studies reporting the most reliable findings. Then we evaluate the more sparse literature focused on 1H-MRS-detected neurometabolic effects of various treatment approaches in psychiatric populations. Finally we speculate on future developments that may result in translation of these tools to improve the treatment of psychiatric disorders.     

Antidepressant chronotherapeutics for bipolar depression

Chronotherapeutics refers to treatments based on the principles of circadian rhythm organization and sleep physiology, which control the exposure to environmental stimuli that act on biological rhythms, in order to achieve therapeutic effects in the treatment of psychiatric conditions. It includes manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance, and controlled exposure to light and dark. The antidepressant effects of chronotherapeutics are evident in difficult-to-treat conditions such as bipolar depression, which has been associated with extremely low success rates of antidepressant drugs in naturalistic settings and with stable antidepressant response to chronotherapeutics in more than half of the patients. Recent advances in the study of the effects of chronotherapeutics on neurotransmitter systems, and on the biological clock machinery, allow us to pinpoint its mechanism of action and to transform it from a neglected or “orphan” treatment to a powerful clinical instrument in everyday psychiatric practice.     

Common genetic risk factors for psychiatric and simatic disorders

There is increasing knowledge about considerable comorbidity between psychiatric and somatic diseases, questioning whether variations in genes could be predisposing factors for both conditions. With respect to the multiple interactions between brain and body investigations have centered on variants in several candidate genes for proteins that mediate these interactions and therefore also have implications in psychiatric disorders. The available data, although still preliminary and rare, indicate the importance of polymorphic variants in genes coding for the serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT), the 5-HT(2A) receptor, proinflammatory cytokines, and the angiotensin-converting enzyme (ACE) in migraine, fibromyalgia, cardiovascular disorders, and psychiatric conditions. The role played by these various polymorphisms remains to be determined, as does whether they are indicative of common pathophysiological mechanisms or identify a subgroup of patients with somatic disorders that are more closely related to psychiatric symptoms. Nevertheless, they do at least illustrate the potential influence of genetic differences on illness course and treatment outcome, and might be a rational approach to drug development and treatment paradigms.     

Hormone treatment of depression

There is a well-established relationship between alterations of various hormonal systems and psychiatric disorders, both in endocrine and psychiatric patients. This has led to clinical and research studies examining the efficacy of the different hormones for treatment of depression. These data will be reviewed with particular regard to the thyroid, gonadal, pineal, and adrenal cortex hormones. The data generally provide limited, but varying evidence for the antidepressant efficacy of these hormones.     

Neuropsychiatry of Huntington's disease

Psychiatric manifestations are an integral part of Huntington's disease. They may be divided into those syndromes which resemble idiopathic disorders, but for which HD patients may be particularly at risk, those constellations which are peculiar to HD and related conditions, such as the executive dysfunction syndrome, and those symptoms that can truly be regarded as nonspecific, such as delirium. Most of these problems are believed to arise from subcortical neuropathologic changes. Major depression is a common psychiatric diagnosis, but the executive dysfunction syndrome, a difficult-to-define condition characterized by often simultaneous apathy and disinhibition, may be even more widespread. There are no large controlled studies of psychiatric treatments in HD, but case series, anecdotal reports, and clinical experience indicate that many of these syndromes respond readily to treatment. Further study of the neuropsychiatry of HD may help to reveal the underpinnings of psychiatric conditions found in the general population.     

Treatment resistant depression as a failure of brain homeostatic mechanisms: Implications for deep brain stimulation

Given the profound negative public health effects of major depressive disorder (MDD), and data suggesting only modest effectiveness of existing psychological and pharmacological treatments for this condition, there has been increasing interest in exploring the antidepressant potential of non-pharmacological, brain-based interventions, such as deep brain stimulation (DBS). The use of the DBS for psychiatric indications follows a decade of data suggesting that DBS is an effective, evidence-based strategy for the treatment of movement disorders such as Parkinson's disease. At the present time there is open-label case series data to suggest that DBS in the subgenual cingulate gyrus, ventral caudate/ventral striatum, and the nucleus accumbens, is associated with antidepressant effects in individuals who fail to respond to conventional treatments for MDD. However a number of unresolved issues about the optimal use of DBS for MDD remain, such as the optimal anatomical placement of the electrodes and the mechanisms of its antidepressant effects. This review summarizes the clinical experience of DBS for treatment resistant depression (TRD). The rationale for the use of DBS for TRD is reviewed in the context of the growing neuroimaging literatures exploring the biomarkers of antidepressant response, and the neural substrates of emotional regulation in both normal and pathological states.     

Cognitive Functioning in Psychiatric Disorders Following Deep Brain Stimulation

BackgroundDeep brain stimulation (DBS) is routinely used as a treatment for treatment-refractory Parkinson's disease and has recently been proposed for psychiatric disorders such as Tourette syndrome (TS), obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Although cognitive deterioration has repeatedly been shown in patients with Parkinson's disease following DBS, the impact of DBS on cognitive functioning in psychiatric patients has not yet been reviewed.ObjectiveReviewing the available literature on cognitive functioning following DBS in psychiatric patients.MethodsA systematic literature search in PubMed, EMBASE and Web of Science, last updated in September 2012, found 1470 papers. Abstracts were scrutinized and 26 studies examining cognitive functioning of psychiatric patients following DBS were included on basis of predetermined inclusion criteria.ResultsTwenty-six studies reported cognitive functioning of 130 psychiatric patients following DBS (37 TS patients, 56 OCD patients, 28 MDD patients, 6 patients with Alzheimer's disease, and 3 patients with other disorders). None of the studies reported substantial cognitive decline following DBS. On the contrary, 13 studies reported cognitive improvement following DBS.ConclusionPreliminary results suggest that DBS in psychiatric disorders does not lead to cognitive decline. In selected cases cognitive functioning was improved following DBS. However, cognitive improvement cannot be conclusively attributed to DBS since studies are hampered by serious limitations. We discuss the outcomes in light of these limitations and offer suggestions for future work.     

Assessment and treatment of mood disorders in the context of substance abuse

Recognition and management of mood symptoms in individuals using alcohol and/or other drugs represent a daily challenge for clinicians in both inpatient and outpatient treatment settings. Diagnosis of underlying mood disorders in the context of ongoing substance abuse requires careful collection of psychiatric history, and is often critical for optimal treatment planning and outcomes. Failure to recognize major depression or bipolar disorders in these patients can result in increased relapse rates, recurrence of mood episodes, and elevated risk of completed suicide. Over the past decade, epidemiologic research has clarified the prevalence of comorbid mood disorders in substance-dependent individuals, overturning previous assumptions that depression in these patients is simply an artifact of intoxication and/or withdrawal, therefore requiring no treatment. However, our understanding of the bidirectional relationships between mood and substance use disorders in terms of their course(s) of illness and prognoses remains limited. Like-wise, strikingly little treatment research exists to guide clinical decision making in co-occurring mood and substance use disorders, given their high prevalence and public health burden. Here we overview what is known and the salient gaps of knowledge where data might enhance diagnosis and treatment of these complicated patients.     

Longitudinal neuropsychological outcomes in treatment-resistant depression following bed nucleus of the stria terminalis-area deep brain stimulation: a case review

ABSTRACT

Studies have demonstrated the effectiveness of deep brain stimulation (DBS) as a treatment modality for psychiatric conditions. We present a case reviewing the longitudinal neuropsychological performance outcomes following bed nucleus of the stria terminalis-area (BNST) DBS in a patient with treatment-resistant depression (TRD). The cognitive safety of DBS is well documented for various targets, however cognitive outcomes of BNST-area DBS have not been extensively reported for patients with TRD. Neuropsychological assessment was conducted pre- and post-DBS. Twelve months following DBS, augmented general cognitive performance was observed with significant changes in specific domains.     

Experimental animal models for the simulation of depression and anxiety

An impressive number of animal models to assess depression and anxiety are available today. However, the relationship between these models and the clinical syndromes of depression and anxiety is not always clear. Since human anxiety disorders represent a multifactorial phenomenon frequently comorbid with major depression and/or other psychiatric problems, the chance of creating animal models which consistently reflect the human situation is quite poor. When using experimental models to understand homologies between animal and human behavior, we have to consider the context in which an animal is investigated, and both the functional significance and relevance of the behavioral parameters that are quantified. Moreover, gender and interindividual and interspecies variabilities in behavioral responses to the test situation and in the sensitivity to pharmacological treatments are potential sources for confounding results. In the past, these aspects have been often neglected in preclinical approaches to behavioral pharmacology and psychopharmacology. A pragmatic approach of combined preclinical and clinical efforts is necessary to imitate one or more aspects relevant to pathological anxiety disorders and depression. The resulting models may identify central nervous processes regulating defined behavioral output, with the potential to develop more effective treatments.     

Synthetic neurosteroids on brain protection

Neurosteroids, like allopregnanolone and pregnanolone, are endogenous regulators of neuronal excitability. Inside the brain, they are highly selective and potent modulators of GABAA receptor activity. Their anticonvulsant, anesthetics and anxiolytic properties are useful for the treatments of several neurological and psychiatric disorders via reducing the risks of side effects obtained with the commercial drugs. The principal disadvantages of endogenous neurosteroids administration are their rapid metabolism and their low oral bioavailability. Synthetic steroids analogues with major stability or endogenous neurosteroids stimulation synthesis might constitute promising novel strategies for the treatment of several disorders. Numerous studies indicate that the 3α-hydroxyl configuration is the key for binding and activity, but modifications in the steroid nucleus may emphasize different pharmacophores. So far, several synthetic steroids have been developed with successful neurosteroid-like effects. In this work, we summarize the properties of various synthetic steroids probed in trials throughout the analysis of several neurosteroids-like actions.