Current Psychiatry Reviews - Volume 2, Issue 1, 2006

I am delighted to assume the helm as Editor-in-Chief of Current Psychiatry Reviews and would like to use this editorial as both a brief introduction and to outline my vision for CPSR. I have focused my career on academic psychiatry for the assessment and treatment of mood disorders, both unipolar and bipolar. For the past decade, my primary research activities have been centered on various topics in therapeutics, including research on older and newer antidepressants (Thase, Rush, and Trivedi, 1995; Thase, Entsuah and Rudolph, 2001; Thase et al., 2005), focused psychotherapies (Thase et al., 1996; Thase et al., 1997a), and their combinations (Thase et al., 1997b; Thase et al., 2002), as well as the methodology of clinical trials (Thase, 1999; Thase, 2002). In early 2006, I will quietly celebrate the 30th anniversary of publishing my first peer-reviewed paper (Thase and Moss, 1976). This small randomized clinical trial compared several behavioral methods to treat simple phobia (excessive fear of a nonpoisonous snake) in 30 college student volunteers. Oh, how the content and process of clinical research has changed across the intervening years! There have been mind-boggling advances in neuroscience; research strategies that were in their infancy in the mid-1970s, ranging from molecular genetics to neuroimaging, have clearly come of age and now define the "cutting edge" of research on the mechanisms of vulnerability, pathophysiology, and therapeutic actions on the major mental disorders. Had our little snake phobia study been conceived in 2005, we might have studied how a behavioral intervention leads to reallocation of cerebral blood flow and energy consumption, examined the relationship between genotypes and the persistence of fearfulness, or assessed whether sustained reduction of fearfulness affects brain derived neurotrophic factor levels. Better understanding of the impact of various biases on research results also have emerged, as well as more sophisticated approaches to statistical analyses. In particular, three topics of great relevance to the readers of CPSR come to mind: 1) the pernicious influence of the "file drawer effect" - the selective publication of positive reports and, conversely, the suppression of negative ones - on reviews of the literature; 2) the endemic problem created by Type II error, i.e., when inadequate statistical power leads to the false conclusion that "not statistically significantly different" actually means that there is no difference; and 3) the impact that one's beliefs, allegiances, and affiliations can have on influencing the results of both quantitative research and qualitative reviews. Given the proliferation of journals and the veritable explosion of research results, now more than ever before there is great need for concise, accessible and unbiased reviews that summarize and - whenever possible - systematically synthesize bodies of evidence. Hence, the mission and aims of CPSR: to provide rapid publication of the most up-to-date reviews of the latest advances in clinical psychiatry broadly defined. Whereas our field's most prestigious journals may publish one or two review papers in each issue, each issue of CPSR will include 10 or more such reviews, with sufficient breadth of coverage to interest both generalists and ultrasubspecialists alike. To help accomplish these goals, I am proud to say that we have assembled a truly outstanding international Editorial Advisory Board, which includes experts spanning all relevant domains of research in psychiatry, including psychopharmacology, psychotherapy, epidemiology, nosology, child psychiatry, geriatric psychiatry, psychotherapy, forensics, and clinical and molecular genetics. Please help me to keep this stellar Board busy with a steady stream of manuscripts - I look forward to the day in which our publisher, Bentham Science Publishers, Ltd., is obliged to make CPSR a monthly enterprise!

The experience of cancer represents a unique challenge to both the physical and psychological health of the individual. High levels of distress are common in cancer patients irrespective of the type of pathology. However, the physiological aspects of the disease process may be a source of confound in the psychiatric screening process, thereby reducing the accuracy of case identification. The current review examines the salient factors which should be considered by clinicians when screening for clinically significant psychological distress. The review will evaluate the strengths and limitations of contemporary screening instruments within this context and suggest approaches to maximize screening accuracy in this clinical group. Finally, the review will consider issues in the efficiency of the referral pathway to liaison psychiatry services for those patients positively screened. Implications for current psychiatric practice and the direction of future research are also discussed.

Neuropsychological studies have shed light on several important aspects of obsessive-compulsive disorder (OCD). Along with neuroimaging and information processing approaches, it has contributed to delineate some of the most instigating pathophysiological models of OCD and to strengthen its diagnostic validity. Lately, neuropsychological studies have also emerged as a potentially relevant research area for therapeutics. In this review, we described the nature of the executive dysfunctions associated with OCD and theorized how they may account for the characteristic memory and visuoconstructive/visuospatial impairments found in patients suffering from this disorder. We also examined the concepts of implicit memory, meta-memory, memory for actions, memory bias, reality monitoring, and the multiple ways these functions may be altered in patients with OCD. The role of cognitive dysfunctions as potential predictors of treatment response to either pharmacological approaches (e.g. serotonin reuptake inhibitors) or to cognitive-behavior therapies (i.e. exposure and response prevention) in patients with OCD was also discussed. Finally, we argued that cognition might be an area of particular vulnerability to the negative effects of the anti-obsessional drugs and of the neuroanatomically-based approaches (neurosurgery and deep-brain stimulation).

In recent years transgenic studies in mice, in particular those utilizing gene knockout techniques, have greatly contributed to our understanding of the molecular mechanisms of drug reward and drug abuse. Many of the initial gene knockouts that have been created focused on the initial molecular targets of drugs of abuse such as the μ opiate receptor (MOR) for morphine, the dopamine transporter (DAT) for cocaine and the vesicular monoamine transporter 2 (VMAT2) for amphetamine. These met with varying degrees of success; for instance, although gene deletion of MOR eliminated virtually all of the effects of morphine, the effects of cocaine were eliminated only by combined deletion of DAT and the serotonin transporter (SERT). However, such studies only address the role of these genes in the actions of a single drug, and not potential contributions to the rewarding and addictive properties of drugs of abuse more generally. Studies of MOR KO mice have been done for a number of addictive drugs and it has become apparent that MOR KO affects the rewarding consequences of a wide range of addictive substances. This contrasts quite sharply with the consequences of other gene deletions, including deletion of the other opiate receptor genes. Furthermore, this conclusion suggests that variants in the MOR gene itself or variation in MOR gene expression may influence susceptibility to drug abuse and provide a common molecular target for treating a wide range of addictions.

Electroconvulsive therapy (ECT) is still the most effective treatment not only for psychotic depression, but also for treatment of resistant or other severe forms of major depressive episodes. Nevertheless, the exact nature of the therapeutic effect of ECT is unknown. Modern theories of depression suggest changes of synaptic plasticity especially within the hippocampus. It was hypothesized that such changes may be reflected in changes of proton magnetic resonance spectroscopy (1H MRS) detectable signals. The current literature on 1H MRS studies on ECT effects is small with a large diversity of MRS methods applied, brain regions studied and metabolite changes found. Nevertheless, there is good evidence that changes in neurometabolite concentrations are induced by ECT that can be non invasively monitored by 1H MRS. There also are pioneering 1H MRS studies on animal models of depression: the Learned Helplessness model in rats and the chronic social stress model in tree shrews. The proposed review will summarize the current MRS findings in humans and animals and discuss possible interpretations.

Suicide is a major public concern and in the teenage population it is the third leading cause of death. Its neurobiology is not well-understood, but recent postmortem brain studies have provided greater understanding of the neurobiological abnormalities associated with suicide. Earlier postmortem brain studies focused on monoamine receptor subtypes, namely, serotonin, e.g., (5HT)1A, 5HT2A, and adrenergic receptors. Later, various components of the signaling cascades to which these receptors are linked were examined; 5HT2A or α1-adrenergic receptors are linked to the phosphoinositide (PI) signaling system, and β-adrenergic receptors are linked to the adenylyl cyclase (AC) system. These studies revealed abnormalities in the components of the signaling systems: G proteins, the effectors phospholipase C (PLC) and AC, or second and third messengers systems, such as protein kinase C (PKC) and protein kinase A (PKA). Further studies found that downstream transcription factors, such as cAMP-response-element-binding protein (CREB), were also affected. Here we critically review the studies, focusing primarily on monoamine receptors and the components of PI and AC signaling cascades in suicide, primarily in postmortem brain. These studies provide a better understanding of the pathophysiological abnormalities associated with suicide and may lead to new therapeutic agents targeting specific sites in the signaling cascade.

Despite the availability of a wide range of different drug classes for the management of psychiatric disorders, the efficiency of drug treatment is far from optimal. Regardless of the initial choice and dose of standard psychiatric medication, about 30-50% of patients will not respond sufficiently to acute treatment while others suffer from severe adverse drug reactions. The patient-to-patient differences in drug response can be explained on the basis of variability in drug pharmacokinetic and pharmacodynamic processes. The involvement of the human polycyclic aromatic hydrocarbon (PAH)-inducible CYP1A2 in the metabolism of several psychotropic drugs is increasingly acknowledged. Currently, it is well-known that this enzyme shows a wide interindividual variability, but controversy has long surrounded the issue of a polymorphic distribution of the enzyme activity leading to pronounced differences in drug response. Moreover, whether genetic polymorphism and/or environmental factors play a definitive role has not yet unequivocally established. On the other hand, combination pharmacotherapy is commonly used in clinical psychiatry, and the CYP1A2 enzyme is the target of many clinically relevant drug interactions. This review is dealing with factors that could better explain patient-to-patient differences in drug response to psychotropic drugs, including CYP1A2 genetic polymorphisms, environmental factors as well drug interactions modulating the CYP1A2 enzyme activity.

Sex-based pharmacotherapy is a new research and clinical area which could be characterized by the inclusion of sex-related variables in clinical, research and educational issues with respect to pharmacotherapy. In this article we will review the studies that evaluate the treatment of schizophrenia with respect to sex considerations. First we will report the findings about sex differences in response to treatment: pharmacokinetic sex differences and differences in effectiveness of response to antipsychotics. We will further review the studies that evaluate the use of estrogens as an adjuvant treatment in women with schizophrenia: in patients with premenstrual worsening of symptoms or in resistant forms of the illness. Also, the possible use of raloxifene (a selective estrogen receptor modulator) as an adjuvant treatment in some postmenopausal schizophrenic women will be discussed. Finally we will review the endocrinal/sexual adverse effects of antipsychotics in women.

Dopamine and noradrenaline in the prefrontal cortex modulate superior cognitive functions and are implicated in the aetiology of depressive and psychotic symptoms. Experimental evidence reveals parallel variations in extracellular concentration of both catecholamines in the cerebral cortex. In this review, data are presented suggesting that extracellular dopamine in the cerebral cortex originates not only from dopaminergic terminals but also from noradrenergic ones, where it acts both as precursor for noradrenaline and as co-transmitter. Since the release of noradrenaline is controlled by alpha2-autoreceptors, it follows that release and extracellular concentration of both dopamine and noradrenaline in the cerebral cortex are controlled by alpha2-autoreceptors and noradrenaline transporter, whereas dopamine receptors and dopamine transporter do not seem to be involved in these processes. Atypical antipsychotics such as clozapine, and antidepressants such as mirtazapine, increase noradrenaline and dopamine release throughout the cerebral cortex, but not, or to a lesser extent, in subcortical areas. On the other hand, D2 selective drugs such as haloperidol, are potent in increasing dopamine levels in subcortical dopaminergic areas but are ineffective on dopamine and noradrenaline levels in the prefrontal cortex. Local stimulation or inhibition of locus coeruleus neurons by means of drug perfusion or electrical stimulation gives rise to parallel variations of noradrenaline and dopamine levels in the cerebral cortex, but not in prevalently dopaminergic subcortical areas. Extracellular dopamine of noradrenergic origin might represent the major portion of total extracellular dopamine not only in cortices with scarce dopaminergic innervation, such as the parietal and occipital cortex, but also in the densely innervated medial prefrontal cortex. In conclusion, drugs acting on the co-release mechanism of noradrenaline and dopamine may represent a tool with which to increase the selective output of dopamine in the cerebral cortex.

Nuclear medicine imaging techniques like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) apply radiolabeled drugs that bind selectively to specific neurotransmitter receptors and transporters such as the serotonin transporter (SERT) in the living human brain. They can help overcome certain limitations of postmortem, platelet and genetic studies of the SERT. This review compares the outcome of those studies with recent neuroimaging findings. The first part of this review deals with the choice of radioligands used to quantify SERT distribution in the human brain. The second part summarizes studies performed to understand the normal physiology of the serotonergic system. Selective serotonin reuptake inhibitors (SSRIs), used to treat a wide range of neuropsychiatric disorders with emotional instability and behavioral control deficits, compete with SERT radioligands and have been investigated in pharmacological PET and SPECT studies in healthy volunteers and patients. Part three reviews SERT imaging studies in patients, which have meanwhile been performed in most disorders that benefit from SSRI treatment. It is hypothesized that serotonin deficits and neuropsychiatric symptoms are linked by the inhibition of involuntary emotional reactions to external and internal stimuli. This could explain, why the consistency of many SERT neuroimaging findings is low, and may help develop individual treatment strategies in therapy-nonresponsive cases and to engineer new drugs for the therapy of neuropsychiatric disorders.

Biological, psychological as well as sociocultural changes occur during the postpartum period and it is a highrisk time for significant psychiatric illness. Postpartum psychiatric disorders had been described for centuries yet these disorders today are still poorly recognized and under-treated. They are currently categorized into postpartum blues, postpartum depression and postpartum psychosis. Panic disorder, Obsessive-Compulsive Disorder, Generalized Anxiety Disorder and Posttraumatic Stress Disorder typify the anxiety disorders of this period. This mini-review describes what is known about postpartum psychiatric disorders in terms of their clinical presentation, etiology and treatment. Lactation issues, the impact on the child, cultural considerations as well as life cycle challenges are also discussed. Significant findings are critically reviewed and potential future research directions that could lead to substantial advancements are identified.

Alcohol abuse and dependence are among the most common psychiatric disorders occurring in adolescents. This article will examine clinically relevant research on the development, diagnosis, course, treatment, and adult outcomes of adolescent alcohol use disorders (AUDs). A developmental history of childhood mental disorders reflecting psychological dysregulation predicts adolescent AUDs. The DSM-IV AUD definitions developed for adults are generally valid for adolescents, although some adolescents with significant alcohol problems are not identified by this diagnostic system. Adolescents with AUDs typically have other substance involvements, comorbid mental disorders, and problematic family relationships. While biomedical complications seen in chronic alcoholic adults are typically absent, acute biomedical complications of intoxication, such as alcohol poisoning or traumatic injury, may contribute to excess mortality in adolescents. Psychosocial interventions promoting abstinence are the most common treatments for AUDs, with credible empirical support available for family-based approaches. While few drug trials have been completed for adolescents with AUDs, pharmacological interventions are available for alcohol withdrawal, craving, and comorbid mental disorders. Some adolescents with AUDs manifest chronic alcoholism in adulthood; many others transition to abstinence or normative drinking. Alcohol abstinence is the primary treatment focus, although other complications need to be addressed and treated to foster optimal clinical outcomes.