Anticonvulsants in the treatment of mood disorders: assessing current and future roles

Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.     

Hypopigmentary skin disorders: current treatment options and future directions

Alterations of skin and hair pigmentation are important features that have warranted treatment from ancient history on up to modern time. In some cultures, even today patients with vitiligo are regarded as social outcasts and are affected considerably both emotionally and physically. This article presents current options and future directions for the treatment of hypopigmentary disorders. Whereas with congenital disorders, such as albinism and phenylketonuria, no causal therapy has been established up to now, several treatment options for acquired hypopigmentary disorders have been investigated. In particular, in vitiligo, one of the most prevalent hypopigmentary disorders, a number of treatment modalities have been employed in the past 30 years. However, most of them are only able to palliate, not cure, the disease. Depending on the distribution of the hypopigmented lesions (localised or generalised) and the state of the disease (active or stable), several therapeutic options, for example phototherapy, surgical skin grafts, autologous melanocyte transplantation and immunomodulators, can be applied alone or in combination. For phototherapy, because of unfavourable results and adverse effects, ultraviolet (UV) A has been largely replaced by narrow-band UVB for repigmentation of generalised vitiligo. Although immunomodulators, such as corticosteroids, have been used both topically and systemically over the past 3 decades for the treatment of disseminated vitiligo, they are only suitable for the treatment of acrofacial and localised forms because of adverse effects. Hence, new immunomodulatory agents, such as calcineurin antagonists, have recently been introduced as new promising tools to treat acquired hypopigmentary disorders. However, all therapeutic approaches are hampered by the fact that the pathophysiology of hypopigmentary disorders is still poorly understood.     

N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects

Introduction: N-acetylcysteine (NAC) is widely known for its role as a mucolytic and as an antidote to paracetamol overdose. There is increasing interest in the use of NAC in the treatment of several psychiatric disorders. The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and inflammatory pathways.

Areas covered: This study reviews the available data regarding the use of NAC in different psychiatric disorders including substance use disorders, autism, obsessive-compulsive spectrum disorders, schizophrenia, depression, bipolar disorder. Promising results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin-picking) disorder. Despite initial optimism, recent findings regarding NAC efficacy in autism have been disappointing.

Expert opinion: These preliminary positive results require further confirmation in larger samples and with longer follow-ups. Given its high tolerability and wide availability, NAC represents an important target to investigate in the field of new adjunctive treatments for psychiatric conditions.     

Anticonvulsants in affective disorders

The current status of anticonvulsant drugs compared to other treatments for the management of affective disorders is evaluated. Data from controlled studies suggest that carbamazepine is superior to placebo, equivalent to neuroleptics, and comparable to lithium for mania, at least in relatively treatment-refractory patients. Carbamazepine may also be useful as an antidepressant and for prophylaxis. Valproate and clonazepam show promise in the treatment of mania and for prophylaxis, but the number of patients studied in controlled trials is small. Lorazepam and other benzodiazepines may be useful antimanic agents, and alprazolam exerts antidepressant effects, although its efficacy relative to the tricyclics is unclear. Electroconvulsive therapy (ECT) is effective for both mania and depression. Established treatments are carbamazepine and ECT for mania and ECT for depression. Still experimental are valproate and clonazepam for mania; carbamazepine and alprazolam for depression; and carbamazepine, ECT, valproate, and clonazepam for maintenance. Combinations with lithium appear promising but await double-blind trials. The place of other anticonvulsants in the treatment of affective disorders is unknown.     

Riluzole in the treatment of mood and anxiety disorders

Recent advances implicate amino acid neurotransmission in the pathophysiology and treatment of mood and anxiety disorders. Riluzole, which is approved and marketed for the treatment of amyotrophic lateral sclerosis, is thought to be neuroprotective through its modulation of glutamatergic neurotransmission. Riluzole has multiple molecular actions in vitro; the two that have been documented to occur at physiologically realistic drug concentrations and are therefore most likely to be clinically relevant are inhibition of certain voltage-gated sodium channels, which can lead to reduced neurotransmitter release, and enhanced astrocytic uptake of extracellular glutamate.Although double-blind, placebo-controlled trials are lacking, several open-label trials have suggested that riluzole, either as monotherapy or as augmentation of standard therapy, reduces symptoms of obsessive-compulsive disorder, unipolar and bipolar depression, and generalized anxiety disorder. In studies of psychiatrically ill patients conducted to date, the drug has been quite well tolerated; common adverse effects include nausea and sedation. Elevation of liver function tests is common and necessitates periodic monitoring, but has been without clinical consequence in studies conducted to date in psychiatric populations. Case reports suggest utility in other conditions, including trichotillomania and self-injurious behaviour associated with borderline personality disorder. Riluzole may hold promise for the treatment of several psychiatric conditions, possibly through its ability to modulate pathologically dysregulated glutamate levels, and merits further investigation.     

Pharmacotherapy of mood disorders and treatment discontinuation

Depression is the most frequent and costly problem in primary care, where most of these patients are seen and treated. In many countries, the public regard antidepressant drugs as 'addictive', partly because of the withdrawal symptoms that can occur when they are discontinued. Indeed, discontinuation (withdrawal) symptoms can follow the stoppage of almost all classes of antidepressants, including selective serotonin receptor inhibitors (SSRIs). This is important because they are widely regarded as drugs of choice for both depression and the anxiety disorders. But is this true withdrawal or merely rebound? The antidepressant discontinuation syndrome is characterised by the time-locked emergence of new, clearly defined and quantifiable signs and symptoms that ensue on stopping or reducing the dose of an antidepressant. Thereby, it meets the criteria for a withdrawal syndrome. The symptoms are not usually severe or protracted. SSRIs vary in their propensity to be associated with a discontinuation syndrome: paroxetine appears to be the most likely. Patients should be warned of the possibility of developing such a reaction, but reassured that it is usually mild and self limiting. Tapering the dose, if practicable, is worthwhile. In severe cases, temporary reinstatement of the SSRI and slower tapering may be necessary. Escalation of antidepressant dosage, or 'street abuse', is rare with antidepressants. The use of antidepressants is generally beneficial, and efforts should be made to optimise our current use of these drugs as well as encouraging the development of newer, better and innovative compounds. To this end, physicians should educate themselves and the public about discontinuation and withdrawal, so that these clinical features can be put in a realistic context.     

Lurasidone: efficacy and safety in the treatment of psychotic and mood disorders

Introduction: Lurasidone ([3aR,4S,7R,7aS]-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1yl-methyl] cyclohexylmethyl]-hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; Latuda®) is a novel benzisothiazole, second-generation antipsychotic drug developed by Dainippon Sumitomo Pharma Corporation in Japan. Similar to other atypical antipsychotics it has a distinctive pharmacodynamic profile,

Areas covered: This review updates reported research findings on the efficacy, safety and tolerability of LRSD for treatment of psychotic and major affective disorders, with meta-analyses. Short-term efficacy of LRSD in schizophrenia is supported by several randomized, controlled trials with daily doses of 40–160 mg, yielding relatively modest symptomatic improvements. Lurasidone has regulatory approval for treatment of undefined duration in schizophrenia. Long-term benefits and effects in schizophrenia, and both short- and long-term use for other psychotic disorders and mania have not been tested. LRSD shows unusual efficacy in acute bipolar depression even without psychotic features. However, trials of adding LRSD to lithium or valproate for bipolar disorder have yielded inconsistent findings.

Expert opinion: Available research findings indicate that LRSD is effective and well-tolerated for short-term treatment of schizophrenia, and for acute bipolar depression. It has low risk of inducing weight-gain, metabolic, or cardiac abnormalities, but its risk of akathisia may exceed that of other modern antipsychotics. Needed is adequate long-term testing in schizophrenia and bipolar disorder and testing for other indications, including against alternative treatments.     

Fluvoxamine in the treatment of menstrually related mood disorders

Twenty women with premenstrual complaints were treated in a double-blind placebo controlled trial during two consecutive menstrual cycles with fluvoxamine, a selective serotonin uptake blocker. A beneficial effect was found on somatic and affective symptoms in both treatment groups, the effect of fluvoxamine being not different from placebo. The results of this study do not support a role for serotonin in menstrually related affective symptoms.     

Lithium long-term treatment in mood disorders: clinical and genetic predictors

Lithium is the most widely used long-term treatment for recurrent mood disorders. Despite its proven efficacy, patients show a variable response, ranging from complete efficacy to no influence at all. This paper reviews possible predictors of response focusing on molecular genetic studies. The functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been associated with lithium long-term efficacy in two independent studies, marginal associations have been reported for tryptophan hydroxylase and inositol polyphosphate 1-phosphatase (INPP1). A number of other candidate genes and anonymous markers did not yield positive associations. Therefore, even though some positive results have been reported, no unequivocal susceptibility gene for lithium efficacy has been identified.     

Managing hyperlipidemia: current and future roles of HMG-CoA reductase inhibitors.

The current and future roles of statins as antilipemic agents for the prevention and management of coronary artery disease (CAD) are reviewed. Therapy with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) substantially reduces total cholesterol and low-density-lipoprotein (LDL) cholesterol concentrations. Large clinical trials have documented the efficacy of statin therapy for both primary and secondary prevention of CAD. Nevertheless, many eligible patients are either untreated or inadequately treated with these agents. In one study, 61% of patients with documented CAD were not treated with a lipid-lowering agent. Large percentages of high-risk patients receiving such agents are not meeting cholesterol goals set by the National Cholesterol Education Program (NCEP). Populations at increased risk for coronary events include patients with diabetes, women, the elderly, and patients with established CAD. Comparative studies have not shown any one agent as clearly superior to the others. Future possibilities for statin use include early treatment of hypercholesterolemia and acute coronary syndromes consistent with guidelines established by NCEP. Many clinicians now believe that an aggressive approach to lowering LDL cholesterol may yield even greater reductions in coronary events. Treatment may reduce the risk of recurrent ischemic events when initiated within 96 hours of hospitalization for acute myocardial infarction or unstable angina and continued for up to four months. Another use may be the management of atherosclerotic cerebrovascular disease. Closer attention to potential adverse effects will be necessary before any expansion in statin use. Statins are highly effective for improving cardiovascular outcomes in high-risk patients but are frequently underused. Pharmacists can help extend the benefits of statins to more patients.     

Role of estrogen in the aetiology and treatment of mood disorders

Worldwide, the prevalence of depression in women is significantly greater than in men. Available data suggest that estrogen, or its absence, is strongly implicated in the regulation of mood and behaviour, as well as in the pathobiology of mood disorders. The multiple effects of estrogens and their complex interactions with the CNS and endocrine system have been well documented, although the specific, multifaceted role of estrogen in each dysphoric state has yet to be elucidated. Several facts suggest that estrogen plays a vital role in the precipitation and course of mood disorders in women. Gender differences in the prevalence of depression first appear after menarche, continue through reproductive age, and dissipate after perimenopause. Periods of hormonal fluctuations or estrogen instability (i.e. premenstrually, postpartum, perimenopausally) have been associated with increased vulnerability to depression among susceptible women. It is plausible that the phenotype of these depressions is distinguishable from those that are not associated with reproductive events or that occur in men. Based on current knowledge, estrogen treatment for affective disorders may be efficacious in two situations: (i) to stabilise and restore disrupted homeostasis - as occurs in premenstrual, postpartum or perimenopausal conditions; and (ii) to act as a psychomodulator during periods of decreased estrogen levels and increased vulnerability to dysphoric mood, as occurs in postmenopausal women. There is growing evidence suggesting that estrogen may be efficacious as a sole antidepressant for depressed perimenopausal women. It is still unclear whether estrogen is efficacious as an adjunct to selective serotonin reuptake inhibitors or as one of the paradigms to manage treatment-resistance depression in menopausal women, but such efficacy is plausible.     

心境稳定剂在精神疾病治疗中的应用

目前临床上常用的心境稳定剂包括锂盐、抗惊厥药物和非典型抗精神病药物。此外,现还新上市了一些具有潜在心境稳定作用的药物或辅助用药。本文概要介绍主要心境稳定剂及其在精神疾病治疗中的应用。     

Translational research in late-life mood disorders: implications for future intervention and prevention research.

Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders.     

Childhood trauma in mood disorders: Neurobiological mechanisms and implications for treatment

A contemporary model for the pathogenesis of mood disorders (bipolar and depressive disorders) involves gene-environmental interaction, with genetic predisposition, epigenetic regulation, and environmental effects. Among multiple environmental factors, the experience of childhood trauma can be connected with the pathogenesis, course and the treatment of mood disorders. Patients with mood disorders have the greater frequency of childhood trauma compared with the general population, and adverse childhood experiences can exert a negative impact on their clinical course. In this article, the neurobiological mechanisms of childhood trauma are presented. The influence of negative childhood experiences on the central nervous system can result in many structural and functional changes of the brain, including such structures as hippocampus and amygdala, associated with the development of bipolar and depressive illnesses. Interaction of several genes with childhood trauma to produce pathological, clinical phenomena in adulthood has been demonstrated, the most important in this respect being the serotonin transporter gene and the FKBP5 gene playing an important role in the pathogenesis of mood disorders. Neurobiological effects can also involve epigenetic mechanisms such as DNA methylation which can exert an effect on brain function over long-term periods. Somatic effects of childhood trauma include disturbances of stress axis and immune-inflammatory mechanisms as well as metabolic dysregulation. Negative childhood experiences may also bear implications for the treatment of mood disorders. In the article, the impact of such experiences on the treatment of mood disorders will be discussed, especially in the context of treatment -resistance to antidepressants and mood-stabilizing drugs.     

Multiple sclerosis: current and future treatment options

Multiple Sclerosis is an inflammatory and degenerative disorder involving the central nervous system. It primarily affects young adults and may result in significant long-term disability. The most common initial presentation is relapsing remitting, followed by a chronic progressive course. In a small number of patients the disease tends to be progressive from onset. Multiple sclerosis has traditionally been described as a demylinating disorder. There is now overwhelming evidence pointing to a very significant degenerative component. Current treatment options include immunomodulating and immunosuppressive agents as well as monoclonal antibodies and target the inflammatory component of the disease resulting in significant reduction in relapses, decrease in MRI lesion load and a modest effect on disability. There are several other biological agents being developed which target different aspects of the immunopathology of multiple sclerosis. This article will review the agents currently used in the treatment of MS and also discuss agents currently under development.     

Second-generation antipsychotic medications in the treatment of mood disorders: focus on aripiprazole

Second-generation antipsychotic medications offer a broader range of therapeutic efficacies than first-generation agents. Consequently, our field has witnessed a rapid expansion of the use of second-generation antipsychotic drugs for several conditions beyond psychosis. The use of second-generation antipsychotic medications has been most pronounced in mood disorders, especially in bipolar disorders. Information about the agents clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole in terms of their efficacy and tolerability in bipolar disorder is now available. Aripiprazole, a new agent whose proposed mechanism(s) of action differs from that of other agents, has been shown in placebo-controlled comparative trials in bipolar patients to be an effective and well tolerated treatment option for this patient group. The role of second-generation antipsychotic medications in the therapeutic armamentarium for bipolar disorders will be determined by clinical experience, by additional phase IV studies and by trials that compare second-generation antipsychotics with each other and also with mood-stabilizing medications. There is also a pressing need for additional information on the long-term efficacy and safety of each second-generation antipsychotic agent during maintenance therapy for bipolar disorders.     

Stiripentol and vigabatrin current roles in the treatment of epilepsy

Introduction: Stiripentol and vigabatrin are the two anticonvulsant drugs currently approved in severe infantile-onset epilepsies, respectively Dravet syndrome and infantile spasms.

Areas covered: For both, the indication was discovered by chance thanks to an exploratory study. Both demonstrated indisputable efficacy through randomized-controlled trials. Stiripentol as adjunctive therapy to clobazam and valproate performed better than placebo, and vigabatrin as first-line monotherapy better than the reference steroid therapy in spasms due to tuberous sclerosis. At one-year treatment vigabatrin and steroids were equally efficient in the other etiologies of spasms. However, it took more than 20 years for both drugs to be approved world-wide.

Expert opinion: Stiripentol suffered from pharmacokinetic potentiation of clobazam, thus raising the question whether it was efficient per se. Finally, animal models and pharmacogenetic data on CYP2C19 confirmed its specific anticonvulsant effect. Stiripentol (in comedication with clobazam and valproate) is therefore to be recommended for Dravet patients. Vigabatrin was found to have a frequent and irreversible retinal toxicity, which required an alternative visual testing to be detected in young children. Today the benefit/risk ratio of vigabatrin as first-line is considered to be positive in infantile spasms, given the severity of this epilepsy and the lack of a safer alternative therapy.     

Anticonvulsants in the treatment of bipolar mania

A series of antiepileptic drugs have been investigated in terms of their ability to treat mania (with later applications for the treatment of bipolar depression and prevention of relapses). These include divalproex, carbamazepine, oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate and zonisamide. Although these drugs are all antiepileptic in action, they bring about these effects by different mechanisms; in particular, their impact on GABA differs significantly. Perhaps for this reason, their impact on mania varies greatly, with double-blind significant results evident only for valproate, carbamazepine and oxcarbazepine. Only valproate and carbamazepine are approved by the US FDA for use in mania; oxcarbazepine has never been found significantly effective in large-scale studies. Of the other options, both gabapentin and topiramate failed in large-scale investigations; tiagabine failed in small sample reports. Although lamotrigine has been successful in the prevention of depression relapse in bipolar disorder, it has not been effective in treating mania. Finally, there are no findings of large scale double-blind studies on the use of levetiracetam and zonisamide. A review of the kinetics, side effects and complications of the antiepileptic drugs indicates that carbamazepine is useful, and has adverse event benefit over all other options. The potential of zonisamide awaits further testing.     

Form to function: current and future roles for atherosclerosis imaging in drug development

There is a pressing need for robust imaging markers to assist in the development of drugs for the treatment of atherosclerosis. Conventional imaging methods provide quantitative and morphological data but may be inadequate for assessing a new generation of therapies that modify plaque biology directly. Here, we compare the main imaging modalities used to image atherosclerosis in the clinical-trial setting, and assess their ability to predict clinical outcomes for a given sample size. We consider how emerging molecular and cellular imaging techniques could offer the possibility to quantify changes in biological function at the level of the plaque, even without gross structural change.