The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

The condition of insomnia: Etiopathogenetic considerations and their impact on treatment practices

Insomnia is conceived as the subjective complaint of reduced sleep quantity and/or quality, even in the absence of objective verification of sleep loss; it is the outcome of the interplay of many environmental, biological, and psychological factors, which can be distinguished into predisposing, precipitating and perpetuating. Predisposing and precipitating factors include various demographic characteristics and the occurrence of psychiatric or somatic illnesses as well as other stressful life events. The perpetuating factors, responsible for the development of chronicity of the complaint of insomnia, mainly involve a 24-hour state of hyperarousal and a vicious cycle of sleeplessness causing fear of sleeplessness which in turn leads to further hyperarousal and more sleeplessness. Particular psychological characteristics, including excessive use of denial and repression as well as a strong propensity for internalisation of emotions, are also among the main factors contributing to the psychophysiological activation and state of hyper-arousability commonly encountered among insomniac patients. The treatment should not only focus on ameliorating sleeplessness, it should also address all those factors that cause and maintain insomnia. An integrative management of insomnia includes education on sleep hygiene measures, behavioural, cognitive and psychodynamic psychotherapies, and the utilization of sleep-promoting drugs. Among the latter, only for the use of benzodiazepine or benzodiazepine-like hypnotics exists sufficient evidence for efficacy as well as adequate information on their side-effect profiles. Thus, these compounds are considered as the drugs of choice for the treatment of insomnia. It is recommended that the use of hypnotic drugs is restricted to the initial period of treatment; they should be rationally utilized within the context of a broad therapeutic program, which is based on a sound doctor-patient relationship and includes sleep hygiene education and the application of certain psychotherapeutic techniques in an individualized manner

The diagnostic validity of the Athens Insomnia Scale

Objective: To provide documentation for the diagnostic validity of the Athens Insomnia Scale (AIS), a self-assessment psychometric tool which has previously shown high consistency, reliability and external validity for the evaluation of the intensity of sleep difficulty. Methods: The AIS was administered to a total of 299 subjects (105 primary insomniacs, 100 psychiatric outpatients, 44 psychiatric inpatients and 50 nonpatient controls) who were also assessed for the ICD-10 diagnosis of “nonorganic insomnia” blindly in terms of the AIS scores. Results: 176 subjects were identified as insomniacs and 123 as noninsomniacs. Logistic regression of AIS total score against the ICD-10 diagnosis of insomnia demonstrated that a score of 6 is the optimum cutoff based on the balance between sensitivity and specificity. When diagnosing individuals with a score of 6 or higher as insomniacs, the scale presents with 93% sensitivity and 85% specificity (90% overall correct case identification). For this cutoff score, in the general population, the scale has a positive predictive value (PPV) of 41% and a negative predictive value (NPV) of 99%. For the same cutoff score, among unselected psychiatric patients, the PPV was found to be 86% and the NPV 92%. Other cutoff scores can be also considered, however, depending on the importance of avoiding false positive or false negative results; for example, for a cutoff score of 10, the PPV in the general population reaches about 90% without the NPV becoming lower than 94%. Conclusion: The AIS can be utilized in clinical practice and research, not only as an instrument to measure the intensity of sleep-related problems, but also as a screening tool in reliably establishing the diagnosis of insomnia. (C) 2003 Elsevier Inc. All rights reserved

Sleep disturbance in unipolar and bipolar depression: Relationship to psychiatric family history

Eighty depressed patients (40 bipolar and 40 unipolar) were personally interviewed in order to assess the relationship of disturbed sleep with psychiatric family history. Complaints of unsatisfactory sleep quantity and/or quality were more common among patients with a negative than among those with a positive family history for either any major psychiatric disorder (74.5 vs. 43.3%, p&lt;0.01) or only a mood disorder (68.4 vs. 43.5%, p&lt;0.05); this was more pronounced in bipolar patients. Results were confirmed when demographic variables and clinical characteristics of the disease were taken into consideration through the use of multiple logistic regression analysis. It is, thus, suggested that the mechanisms underlying disturbed sleep during a major depressive episode are different to those associated with the familial predisposition for depression. Copyright (C) 2003 S. Karger AG, Basel

Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria

Objectives: To describe and validate the Athens Insomnia Scale (AIS). Methods: The AIS is a self-assessment psychometric instrument designed for quantifying sleep difficulty based on the ICD-IO criteria. It consists of eight items: the first five pertain to sleep induction, awakenings during the night, final awakening, total sleep duration, and sleep quality; while the last three refer to well-being, functioning capacity, and sleepiness during the day. Either the entire eight-item scale (AIS-8) or the brief five-item version (AIS-5), which contains only the first five items, can be utilized. The validation of the AIS was based on its administration to 299 subjects: 105 primary insomniacs, 144 psychiatric patients and 50 non-patient controls. Results: Regarding internal consistency, for both versions of the scale, the Cronbach’s alpha was around 0.90 and the mean item-total correlation coefficient was about 0.70. Moreover, in the factor analysis, the scale emerged as a sole component. The test-retest reliability correlation coefficient was found almost 0.90 at a 1-week interval. As far as external validity is concerned, the correlations of the AIS-8 and AIS-5 with the Sleep Problems Scale were 0.90 and 0.85, respectively. Conclusion: The high measures of consistency, reliability, and validity of the AIS make it an invaluable tool in sleep research and clinical practice. (C) 2000 Elsevier Science Inc. All rights reserved

Rapid cycling bipolar disorder: biology and pathogenesis

The rapid cycling (RC) pattern of a mood disorder is characterized by at least four affective episodes (manic, hypomanic or major depressive) during the last year; different episodes must be demarcated by a switch to an episode of opposite polarity or by a period of remission of at least 2 months. RC is very rare in unipolar patients; its prevalence, however, in bipolar patients is 10-30 % with the majority being women (70-90 %). Patients with RC usually suffer from bipolar II disorder with onset with a depressive episode. Genetic studies have not convincingly shown that the condition is genetically determined. Major abnormalities of thyroid function have not been shown to be related to RC, but recent studies propose that latent subclinical hypothyroidism might play a role in the acceleration of cycles. Perturbations of the circadian biological and social rhythms might influence the expression of RC. No major effect of the menstrual cycle has been found. Despite the absence of firm empirical data, the possible contribution of the kindling phenomenon on the acceleration of cycles cannot be excluded. Finally, there is evidence that RC can be induced by the use of antidepressant drugs, especially for women