Are all antidepressants alike?

Antidepressants are indicated in about 40 different disorders, including mood disorders, anxiety disorders, and other disorders. We propose to call these disorders antidepressani-responsive disorders (ARDs). We describe the clinical and biological criteria that differentiate the antidepressants. Although antidepressants share the same clinical efficacy in most ARDs, the configuration of adverse drug reactions varies widely. The recent antidepressants should be preferred to the tricyclic antidepressants as first-line treatment because of their lesser risk of severe adverse drug reactions. However, several recent antidepressants have been associated with severe complications such as the serotonin syndrome and the withdrawal syndrome. Patient characteristics should be included as a criterion to predict both unwanted and favorable effects.     

Pharmacotherapy of anxiety disorders: a critical review

Given the enormous contribution of anxiety disorders to the burden of disease, it is key to optimize their prevention and treatment. In this critical review we assess advances in the pharmacotherapy of anxiety disorders, as well as remaining challenges, in recent decades, the field has seen rigorous clinical trial methods to quantify the efficacy and safety of serendipitously discovered agents, more focused development of medications with selective mechanisms of action, and the gradual translation of insights from laboratory research into proof-of-principle clinical trials. On the positive side, a considerable database of studies shows efficacy and relative tolerability of the selective serotonin reuptake inhibitors in the major anxiety disorders, and secondary analyses of such datasets have informed questions such as optimal definition of response and remission, optimal dose and duration, and comparative efficacy of different agents. Significant challenges in the field include barriers to appropriate diagnosis and treatment of anxiety disorders, failure of a significant proportion of patients to respond to first-line pharmacotherapy agents, and a limited database of efficacy or effectiveness studies to guide treatment in such cases.     

Cognitive-behavioral therapy for anxiety disorders: an update on the empirical evidence

A large amount of research has accumulated on the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for anxiety disorders including posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and specific phobia. The purpose of the current article is to provide an overview of two of the most commonly used CBT methods used to treat anxiety disorders (exposure and cognitive therapy) and to summarize and discuss the current empirical research regarding the usefulness of these techniques for each anxiety disorder. Additionally, we discuss the difficulties that arise when comparing active CBT treatments, and we suggest directions for future research. Overall, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but dismantling studies are needed to determine which specific treatment components lead to beneficial outcomes and which patients are most likely to benefit from these treatment components.     

Psychopharmacology of anxiety disorders

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.     

Cognitive behavioral therapy in anxiety disorders: current state of the evidence

A plethora of studies have examined the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for adult anxiety disorders. In recent years, several meta-analyses have been conducted to quantitatively review the evidence of CBT for anxiety disorders, each using different inclusion criteria for studies, such as use of control conditions or type of study environment. This review aims to summarize and to discuss the current state of the evidence regarding CBT treatment for panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Overall, CBT demonstrates both efficacy in randomized controlled trials and effectiveness in naturalistic settings in the treatment of adult anxiety disorders. However, due to methodological issues, the magnitude of effect is currently difficult to estimate. In conclusion, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but more high-quality studies are needed to better estimate the magnitude of the effect.     

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.     

Deep brain stimulation in the treatment of depression

Major depressive disorder is a worldwide disease with debilitating effects on a patient''s life. Common treatments include pharmacotherapy, psychotherapy, and electroconvulsive therapy. Many patients do not respond to these treatments; this has led to the investigation of alternative therapeutic modalities. Deep brain stimulation (DBS) is one of these modalities. It was first used with success for treating movement disorders and has since been extended to the treatment of psychiatric disorders. Although DBS is still an emerging treatment, promising efficacy and safety have been demonstrated in preliminary trials in patients with treatment-resistant depression (TRD). Further, neuroimaging has played a pivotal role in identifying some DBS targets and remains an important tool for evaluating the mechanism of action of this novel intervention. Preclinical animal studies have broadened knowledge about the possible mechanisms of action of DBS for TRD, Given that DBS involves neurosurgery in patients with severe psychiatric impairment, ethical questions concerning capacity to consent arise; these issues must continue to be carefully considered.     

Chronobiology and mood disorders

The clinical observations of diurnal variation of mood and early morning awakening in depression have been incorporated into established diagnostic systems, as has the seasonal modifier defining winter depression (seasonal affective disorder, SAD). Many circadian rhythms measured in depressive patients are abnormal: earlier in timing, diminished in amplitude, or of greater variability. Whether these disturbances are of etiological significance for the role of circadian rhythms in mood disorders, or a consequence of altered behavior can only be dissected out with stringent protocols (eg, constant routine or forced desynchrony). These protocols quantify contributions of the circadian pacemaker and a homeostatic sleep process impacting on mood, energy, appetite, and sleep. Future studies will elucidate any allelic mutations in "circadian clock" -related or "sleep"-related genes in depression. With respect to treatment, antidepressants and mood stabilizers have no consistent effect on circadian rhythmicity. The most rapid antidepressant modality known so far is nonpharmacological: total or partial sleep deprivation in the second half of the night. The disadvantage of sleep deprivation, that most patients relapse after recovery sleep, can be prevented by coadministration of lithium, pindolol, serotonin (5-HT) reuptake inhibitors, bright light, or a subsequent phase-advance procedure. Phase advance of the sleep-wake cycle alone also has rapid effects on depressed mood, which lasts longer than sleep deprivation. Light is the treatment of choice for SAD and may prove to be useful for nonseasonal depression, alone or as an adjunct to medication. Chronobiological concepts emphasize the important role of zeitgebers to stabilize phase, light being the most important, but dark (and rest) periods, regularity of social schedules and meal times, and use of melatonin or its analogues should also be considered. Advances in chronobiology continue to contribute novel treatments for affective disorders.     

Serotonin-related pathways and developmental plasticity: relevance for psychiatric disorders

Risk for adult psychiatric disorders is partially determined by early-life alterations occurring during neural circuit formation and maturation. In this perspective, recent data show that the serotonin system regulates key cellular processes involved in the construction of cortical circuits. Translational data for rodents indicate that early-life serotonin dysregulation leads to a wide range of behavioral alterations, ranging from stress-related phenotypes to social deficits. Studies in humans have revealed that serotonin-related genetic variants interact with early-life stress to regulate stress-induced cortisol responsiveness and activate the neural circuits involved in mood and anxiety disorders. Emerging data demonstrate that early-life adversity induces epigenetic modifications in serotonin-related genes. Finally, recent findings reveal that selective serotonin reuptake inhibitors can reinstate juvenile-like forms of neural plasticity, thus allowing the erasure of long-lasting fear memories. These approaches are providing new insights on the biological mechanisms and clinical application of antidepressants.     

The effectiveness of anticonvulsants in psychiatric disorders

Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, affective disorders, bipolar affective disorders in particular, and, to some extent, personality disorders. A further area in which neurology and psychiatry overlap is pain conditions, in which some anticonvulsants, and also typical psychiatric medications such as antidepressants, are helpful. From the beginning of their psychiatric use, anticonvulsants have also been used to ameliorate specific symptoms of psychiatric disorders independently of their causality and underlying illness, eg, aggression, and, more recently, cognitive impairment, as seen in affective disorders and schizophrenia. With new anticonvulsants currently under development, it is likely that their use in psychiatry will further increase, and that psychiatrists need to learn about their differential efficacy and safety profiles to the same extent as do neurologists.     

Contribution of sleep research to the development of new antidepressants

Several sleep anomalies are known to accompany depression and other psychiatric disorders, and to be partially modified by drugs efficient on clinical symptoms. Many puzzling theoretical questions remain, even after 30 years of research, because these drugs do not act in a uniform way: some reduce slow-wave sleep while others increase it some prolong rapid-eye movement sleep latency, while others do not. The relationship between insomnia and depression is likely to be a close one, since a large majority of patients with depression suffer insomnia, and that insomnia can predate depression by a few years. However, questions remain here, too, since sleep deprivation is also an effective means to combat depression, and some patients present with hypersomnia rather than insomnia. This review details the action of all current classes of antidepressants on sleep. It examines the predictive value of baseline electronencephalographic sleep symptoms or early modifications due to treatment for eventual clinical efficiency. We will also discuss the two main theories on the relationship between sleep and depression. The action on sleep of all new drugs-and antidepressants in particular-is carefully examined during development, for insomnia is currently considered to be a major health con-insomnia is currently considered to be a major health concern in industrialized countries.     

Cellular and molecular mechanisms in the long-term action of antidepressants.

The hypotheses on the pathophysiology of depression /mood disorders and on antidepressant mechanisms have greatly changed in recent years. The classical monoamine hypothesis was revealed to be simplistic, in that it could not explain the temporal delay in the therapeutic action of antidepressants. Converging lines of evidence have shown that adaptive changes in the several mechanisms of neuroplasticity are likely to be the cellular and molecular correlates of therapeutic effect. In this article, several mechanisms of neuroplasticity are analyzed in relation to the mechanism of antidepressants, ranging from changes in gene expression (including neurotrophic mechanisms), to synaptic transmission and plasticity, and neurogenesis. We propose that the current version of the hypothesis of antidepressant mechanism simply be called the “hypothesis of neuroplasticity. ” In the final section, we also briefly review the main current novel strategies in the pharmacology of depression and the new putative targets for antidepressants, with particular emphasis on nonmonoaminergic mechanisms.     

Redesigning antidepressant drug discovery

Antidepressant drug discovery and development have been put on hold by many pharmaceutical companies. The main reason for this is the negative efficacy studies with novel specific drugs. Here I argue that the main obstacles are the absence of gene tests and biomarkers as an integral part of a diagnostic process. Further, too much emphasis has been put on validating drug candidates in animal models of psychiatric disorders. A more rapid transfer of drug candidates into human research is necessary to overcome current obstacles that prevent the discovery of next-generation antidepressants.     

Neurogenetics of emotional reactivity to stress in animals

There is much evidence for the involvement of central monoaminergic systems, the key targets of stress, in the regulation of mood. Animal and human findings indicate that genetics play a role in the etiology of mood disorders, and so we selected divergent inbred rat strains according to their anxiety-related behaviors on exposure to novel environments. We compared these strains for psychoneuroendocrine response to stressors and/or antidepressants. Molecular genetic studies were also performed to localize the genomic regions associated with these strain-dependent anxiety profiles. We then examined human results indicating that allelic variations in the serotonin transporter (5-HTT) may play a role in the etiology of neuroticism and depression. Thus, we compared inbred rat strains for the 5-HTT, with regard to central and peripheral (platelet) protein expression and function, and the consequences of local application of a selective serotonin reuptake inhibitor (SSRI) on extracellular serotonin (5-HT) levels. Our results indicate that spontaneously hypertensive rats and Lewis rats (LEW) selectively diverge in terms of anxiety-related behaviors and that this divergence is located on chromosome 4. The use of social defeat in LEW and the analysis of its psychoneuroendocrine consequences strongly suggest that such a paradigm, which is sensitive to repeated SSRI treatment, models posttraumatic stress disorder. The Wistar-Kyoto rat may be an adequate model to study the consequences of a genetically driven hypersensitivity to stress and noradrenergic antidepressants. Our most recent findings show that the Fischer 344 and LEW strains differ in protein expression and function of hippocampal and platelet 5-HTT; the divergence in protein expression is not due to allelic variations in the gene-coding sequences and leads to marked differences in extracellular 5-HT levels under basal conditions or SSRI. These examples illustrate how the use of inbred rat strains may complement our knowledge on the genetics of behavior, in the same way as the use of transgenic mice.     

Neuropsychiatric consequences of cardiovascular medications

The use of cardiovascular medications can have a variety of neuropsychiatric consequences. Many cardiovascular agents cause higher rates of fatigue and sedation than placebo, and case reports of medication-induced mood syndromes, psychosis, and cognitive disturbances exist for many cardiovascular drugs. Depression has been associated with P3-blockers, methyldopa, and reserpine, but more recent syntheses of the data have suggested that these associations are much weaker than originally believed. Though low cholesterol levels have been associated with depression and suicide, lipid-lowering agents have not been associated with these adverse effects. Finally, cardiovascular medications may have beneficial neuropsychiatric consequences; for example, the use of clonidine in patients with attention deficit-hyperactivity disorder, the use of prazosin for patients with post-traumatic stress disorder; and the use of propranolol for performance anxiety and akathisia.     

Psychiatric aspects of organic sleep disorders

In recent years, a number of studies have attempted to characterize psychological disturbances related to various sleep disorders. The objective of this type of research is to investigate the possibility that psychopathology may represent an etiological factor, a complication, and/or a target for treatment. In addition, disordered sleep can present itself in a complex and atypical fashion in which the primary sleep-related component may not be immediately apparent. This article reviews the evidence for a relationship between organic sleep disorders and psychiatric morbidity. Generally, it can be concluded that organic sleep disorders have a profound negative impact on most domains of health-related quality of life. Results for the sleep disorders that have been studied (narcolepsy idiopathic hypersomnia, sleep apnea/hypopnea syndrome, restless legs syndrome, periodic limb movement disorder, and circadian sleep disorders) show strong evidence for an association with mood disorders. After treatment, depression scores may or may not improve to the level of population norms, suggesting that this relationship is more complex than one of mere cause and effect.     

Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking

There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.     

The epidemiology of anxiety disorders: a review

Epidemiological studies show that anxiety disorders are highly prevalent and an important cause of functional impairment; they constitute the most frequent menial disorders in the community. Phobias are the most common with the highest rates for simple phobia and agoraphobia. Panic disorder (PD) and obsessive-compulsive disorder (OCD) are less frequent (2% lifetime prevalence), and there are discordant results for social phobia (SP) (2%-16%) and generalized anxiety disorder (GAD) (3%-30%). These studies underline the importance of an accurate definition of disorders using unambiguous diagnostic and assessment criteria. The boundaries between anxiety disorders are often ill defined and cases may vary widely according to the definition applied. Simple phobia, agoraphobia, and GAD are more common in vmrnen, while there is no gender différence for SP, PD, and OCD, Anxiety disorders are more common in separated, divorced, and widowed subjects; their prevalence is highest in subjects aged 25 to 44 years and lowest in subjects aged >65 years. The age of onset of the different types of anxiety disorders varies widely: phobic disorders begin early in life, whereas PD occurs in young adulthood. Clinical - rather than epidemiological - studies have examined risk factors such as life events, childhood experiences, and familial factors. Anxiety disorders have a chronic and persistent course, and are frequently comorbid with other anxiety disorders, depressive disorders, and substance abuse. Anxiety disorders most frequently precede depressive disorders or substance abuse, Comorbid diagnoses may influence risk factors like functional impairment and quality of life. It remains unclear whether certain anxiety disorders (eg, PD) are risk factors for suicide. The comorbidity of anxiety disorders has important implications for assessment and treatment and the risk factors should be explored. The etiology, natural history, and outcome of these disorders need to be further addressed in epidemiological studies.     

Bipolar disorder--methodological problems and future perspectives

Since its "rebirth" in 1966, bipolar disorder (BPD) has rapidly come to occupy a central position in the research and treatment of mood disorders. Compared with major depressive disorder (MDD), BPD is a more serious condition, characterized by much more frequent recurrence, more complex comorbidity, and higher mortality. One major problem is the lack of valid definitions in adult and in child psychiatry; the current definitions are unsatisfactory, and heavily favor an overdiagnosis of MDD. Biological research is partially based on those definitions, which have a short half-life. An additional, dimensional, approach, quantifying hypomania, depression, and anxiety by self-assessment and symptom checklists is recommended. A further, related problem is the early recognition of the onset of BPD, especially in adolescence, and the identification of correlates in childhood. Early and timely diagnosis of BPD is necessary to enable prompt intervention and secondary prevention of the disorder. The paper describes the current status and future directions of developing clinical concepts of bipolarity.     

Pharmacological approaches to the treatment of complicated grief: rationale and a brief review of the literature

Complicated grief (CG) is a common and often under-acknowledged cause of profound impairment experienced after the loss of a loved one. Although both clinical and basic research suggests that pharmacological agents might be of use in the treatment of CG, research on pharmacological approaches to this condition is still scarce. Three open-label trials and one randomized trial on bereavement-related depression suggest that tricyclic antidepressants may be effective, although they may be more efficacious for depressive symptoms than for grief-specific symptoms. Four open-label trials (total number of participants, 50) of selective serotonin reuptake inhibitors (SSRIs) have yielded results, providing very preliminary support that they might be effective in the treatment of CG, both as a standalone treatment and in conjunction with psychotherapeutic interventions. These more recent studies have shown an effect on both depression and grief-specific scales. Furthermore, therapeutic interventions for CG may be more effective in conjunction with SSRI administration. Given the small number of pharmacological studies to date, there is a need for randomized trials to test the potential efficacy of pharmacological agents in the treatment of CG.