Quetiapine Add-On Therapy May Improve Persistent Sleep Disturbances in Patients with PTSD on Stabile Combined SSRI and Benzodiazepine Combination: A One-Group Pretest-Posttest Study.

BACKGROUND: To assess potential benefits of quetiapine for persistent sleep disturbances in patients with posttraumatic stress disorder (PTSD) on stable combined SSRI and benzodiazepine therapy, who previously failed to respond to various benzodiazepine and non-benzodiazepine hypnotic adjuvant treatment as well as to first-generation antipsychotic add-on treatment. SUBJECTS AND METHODS: Fifty-two male PTSD outpatients on stable combination treatment with SSRI and benzodiazepines, with persistent sleep disturbances not responding to prescription of zolpidem, flurazepam, nitrazepam, promazine, and levopromazine, were assessed for sleep disturbances improvements after prescription of quetiapine in the evening. Each patient met both ICD-10 and DSM-IV criteria for PTSD. Psychiatric comorbidity and premorbidity were excluded using the Mini-International Neuropsychiatric Interview (MINI). Improvement on the CAPS recurrent distressing dream item, reduction in the amount of time needed to fall asleep, prolongation of sleep duration, and reduction in average number of arousals per night in the last 7 days before the assessment period were used as efficacy measures. RESULTS: All sleep-related parameters improved significantly at the end of a five-week follow-up: sleep duration increased by one hour (p<0.001), sleep latency decreased by 52.5 minutes (p<0.001), median number of arousals per night decreased from two to one (p<0.001), CAPS recurrent distressing dream item median decreased from five to four (p<0.001), and the number of patients dissatisfied with their sleep quality and quantity decreased from 45 to two (p<0.001). CONCLUSION: Quetiapine prescribed in the evening may be successful therapy for persistent sleep disturbances in patients with PTSD and generally good response to an SSRI and benzodiazepine combination, who previously failed to respond to some of the usual hypnotic medication or addition of first-generation antipsychotics: zolpidem, flurazepam, nitrazepam, promazine, and levopromazine.

Association of Functional Polymorphism in TPH2 Gene with Alcohol Dependence and Personality Traits: Study in Cloninger's Type I and Type II Alcohol-Dependent Inpatients.

Alcohol dependence (AD) is a complex disorder with a poorly understood etiology. In this study, we investigated the relationship between genetic variation in the TPH2 gene, which encodes the enzyme responsible for serotonin synthesis in the brain, and both AD and personality traits, with attention to Cloninger's types of AD. The study included 373 healthy control subjects, 206 inpatients with type I AD, and 110 inpatients with type II AD. All subjects were genotyped for the functional polymorphism rs4290270 in the TPH2 gene, and AD patients completed the Tridimensional Personality Questionnaire (TPQ). The AA genotype and the A allele of the rs4290270 polymorphism were more frequent in both patient groups compared with the control group. In addition, a negative association was found between the number of A alleles and TPQ scores for harm avoidance in patients with type II, but not type I, AD. These results support the involvement of genetic variations of the serotonergic system in the pathogenesis of AD, especially type II AD. They also suggest that in a subset of patients, genetic variation of TPH2 could potentially influence the development of AD by affecting the personality trait of harm avoidance.

Changes in platelet serotonin concentration after four weeks of alcohol abstinence depending on the genotype of the serotonin transporter.

BACKGROUND: Alcohol use disorder (AUD) is a psychiatric disorder characterized by excessive and uncontrolled drinking that causes distress and has damaging consequences for men and women of all ages. It is one of the four most disabling diseases and it affects approximately 14.6 million persons in Europe. OBJECTIVES: Objective of this study is to investigate changes in platelet serotonin concentration after four weeks of alcohol abstinence in regards to the genotype of the serotonin transporter. METHODS: A total of 154 patients with AUD were included in the study. Platelet serotonin concentrations were assessed by enzyme-linked immunosorbent assay. Genotype of serotonin transporter promoter polymorphism was determined by the polymerase chain reaction-based method. RESULTS: We did not establish a statistically significant main effect of serotonin transporter polymorphism on platelet serotonin concentration after four weeks of abstinence. CONCLUSION: Aforementioned finding is in line with previous research suggesting a complex relationship between serotonin transporter gene and platelet serotonin levels, and congruent with the well-established genotype interaction with numerous other factors, such as sex, ethnicity, education level, and stressful life events.

Alcohol dependence and polymorphisms of serotonin-related genes: association studies.

Variations in 5HT-related genes contribute to the alterations of serotonergic neurotransmission, which is implicated in the etiopathology of alcoholism. In this preliminary study we have tested polymorphisms of genes involved in 5HT transport and turnover for their association with alcohol dependence. A case group of males with type 2 alcoholism (N=59) and a control group of healthy males (N=282), both of Croatian origin, were analyzed for the frequency distribution of polymorphisms in 5HT transporter (5HTT-VNTR2, 5HTT-LPR), monoamine oxidase A (MAOA-uVNTR) and B (MAOB-A/G) and tryptophan hydroxylase 1 (TPH1 A218C) and 2 (TPH2 G-703T) genes. An increase in the frequencies of 10-repeat allele (p = 0.010; OR = 1.73; 95% CI = 1.14-2.60) and 10/10 genotype (p = 0.006; OR = 2.57; 95% CI = 1.32-5.00) of the 5HTT-VNTR2 polymorphism was found in alcoholic patients. No differences between case and control groups were observed for the other tested polymorphisms. Present results support earlier studies implicating the role of 5HTT gene in alcoholism. The increase of sample size (in progress) is expected to enable search of more subtle differences, as well as re-evaluation of these preliminary findings.

Platelet monoamine oxidase kinetics, alcoholism subtypes and cigarette smoking.

In trying to dissociate the effect of alcohol and tobacco use on platelet monoamine oxidase-B (MAO-B) activity, we compared the enzyme kinetics in controls (n = 66) and alcohol-dependent patients (n = 81), subdivided according to the severity of both, alcohol and tobacco use. Platelet MAO-B kinetics was measured spectrophotofluorimetrically in chronic alcohol intoxication and after 3 weeks abstinence. In alcoholic patients, an increased Michaelis-Menten constant (16%, p < 0.01) was shown, notwithstanding smoking status. Maximal velocity did not differ between patients and controls when adjusted for smoking. In cigarette smokers, a highly significant dose-dependent reduction of platelet MAO velocity (40%, p < 0.001) was demonstrated, with a similar degree of reduction in patients and controls. Tobacco use itself had no influence on MAO affinity. No differences were shown between subtype 1 and 2 alcoholics, or between the day of admission and the 21st day of abstinence. In conclusion, it seems that both, alcohol and tobacco consumption, may contribute to the lowering of overall platelet MAO-B activity. The effect of alcohol is small, due to interference with substrate binding, and not alteration of catalytic activity. In contrast, the effect of cigarette smoking is pronounced and relates to the dose-dependent reduction of platelet MAO velocity, with no influence on its affinity.

Alcohol--health effects, working environment and prevention.

Alcoholism is a growing medical and public health issue both in adults and in the younger generation. It is a multietiological phenomenon influenced by genetic, psychological, cultural and other factors. Alcoholic beverages have traditionally been prepared from various ingredients such as grapes, hops, rice, honey, etc. Drinking prevalence has varied and is more pronounced in women and the youth. Alcoholism is shown to be of neurophysiological etiology and may lead to impairment of all human body systems. The most frequent cause of death in alcoholics are diseases of the cardiovascular system. The problem of alcoholism at workplace is very important since by affecting health and reducing work productivity it leads to accidents, injuries and decreased working capacity. Efficient solving of alcoholism and related problems includes early detection, so it is necessary to orient the health care services towards primary prevention and early interventions.

[Alcoholism--how it affects health and working capacity]. / Ovisnost o alkoholu - posljedice za zdravlje i radnu sposobnost.

Alcoholism is a growing medical and public health issue both in adult and in younger populations. It is a multi-aetiological phenomenon influenced by genetic, psychological, cultural and other factors. Alcoholic beverages have traditionally been prepared from various ingredients, such as grapes, malt, and rice. Drinking prevalence has varied and is more pronounced in women and the youth. Alcoholism is shown to be of neurophysiologic origin and may lead to the impairment of all human body systems. The most frequent cause of death in alcoholics are the diseases of the cardiovascular system. Alcoholism at workplace is a very important issue as it affects health, reduces productivity, and may lead to accidents, injuries and decreased working capacity. Alcohol-related difficulties develop much earlier than the clinical picture. The diagnosis of alcoholism includes early detection of alcohol-related problems, so it is necessary to orient the healthcare services towards primary prevention and early intervention.

NEUROBIOLOGICAL BASES OF ALCOHOL ADDICTION.

Alcohol addiction is a heterogeneous psychiatric disorder according to both phenotype and etiology. Difference in phenotype characteristics manifests in the manner the addiction arises, history of the alcoholic and history of drinking, comorbid disorders, and the phenomenon of abstinence difficulties. Concerning the etiology of alcoholism, the disease itself is considered to be a consequence of an interactive influence of the environment and genetic factors. Numerous researches conducted in the last decades discovered many aspects of the biochemical, cell and molecular bases of alcohol addiction, leading to a conclusion that alcoholism is, like many other addictions, a brain disease. By recognizing alcoholism as a disease which basically implies changes of the neurobiological mechanisms, as well as a clear genetic basis, it was supposed that the disease, having its basis solely in the symptomatology, is essentially heterogeneous. By trying to solve the problem of a clinically heterogeneous nature of the disease during the last fifty years, various sub-classifications of such patients have been suggested. According to Cloninger, subtypes of alcoholism differ also according to changes in the brain neurotransmission systems, i.e. it is supposed that patients suffering from alcoholism type 1 have a more pronounced dopaminergic transmission deficit, while dopaminergic transmission is not disturbed significantly in patients diagnosed with alcoholism type 2, who, however, have a significant lack of serotonergic transmission. In such a way, Cloninger actually presented the basis of the so-called neurobiological alcoholism model. Since he has connected differences in neurotransmission with differences in personality characteristics, this model is also known as the psychobiological model of alcoholism. The characteristic of alcoholism type 1 is avoiding damage (Harm Avoidance, HA) decreased dopamine transmission and increased serotonin transmission, while the significant characteristic of alcoholism type 2 is seeking for excitement (Novelty Seeking, NS), unchanged dopamine transmission and decreased serotonin transmission. These neurochemical differences among alcoholism subtypes represent the basis for a different therapy approach. Intake of alcohol changes different gene expression in the human brain. The inheritance model of alcoholism is not fully explained, however, it is considered that the disease is connected to a larger gene number included in neurotransmission, cell mechanisms and general metabolic function, with a simultaneous influence of the environment. The contribution of genetic factors is stronger in certain types of alcoholism and thus we have been confronted in the last years of alcoholism research with studies researching the connections of some alcoholism subtypes with the polymorphism phenomenon in the genes coding the synaptic proteins included in the alcoholism etiology. The primary role of monoamine oxidase (MAO) in the brain is catalysis of deamination of the oxidative neurotransmitter amines, i.e. serotonin, adrenaline, noradrenaline and dopamine. Thus, this enzyme is the key factor for maintaining cytoplasmic concentration of various neurotransmitters and for regulation of the neurotransmitting synaptic activity. Taken this MAO function into consideration, MAO is the enzyme included in the etiology and pathogenesis of various neuropsychiatric and neurological disorders. The finding of the decreased platelet MAO activity in various psychiatric disorders has brought us to the assumption that this enzyme may be a constitutional/genetic indicator (trait marker) or an indicator of disease condition (state marker) in biologic psychiatry. There are only a few studies of alcohol addiction researching the connections of the MAO coding gene polymorphism and alcoholism; however, these studies are primarily related to the variable number of tandem repeats (VTNR) polymorphism in the regulatory gene region for MAO-A, considered to influence the transcription activity/functionality of the enzyme.

Epidemiological study of suicide in Croatia (1993-2003)--comparison of Mediterranean and continental areas.

The aim of this study is to analyze eventual differences in characteristic of suicide between two areas of the Republic of Croatia, mediterranean and continental, according to the following variables: suicidal rates, season, month, day, method, places, socioeconomic variables such as gender, ages, marital status, employment, education, and psychiatric or medical characteristic. Data were collected from the Suicide register of the Ministry of Interior, and Croatian Bureau of Statistic. Analysis was done on all suicide cases committed in the period 1993-2003. According to the Suicide Register of Ministry of Interior, 11,359 suicides were reported in period between 1993 and 2003. The average suicide rate in the Mediterranean area was lower (16.44 suicides per year) than in continental area of Croatia (26.34 suicides per year). Suicide committers in the Mediterranean area was statistically significant younger than suicide committers in the continental area of Croatia. In the continental area male suicide committers were more often than in the Mediterranean area of Croatia. In the Mediterranean area suicide committers were in most cases with high school education while in continental area of Croatia most cases of suicide committers were with elementary school education. Alcohol dependence, family conflicts, and medical disorders were more often present as suicidal motive in suicide committers in continental area of Croatia than in the Mediterranean area where undefined and unknown reason of suicide is present in majority of suicide cases. Cold steel, drowning, and jumping from height were more often present as suicidal method in the Mediterranean area of Croatia opposite to continental area of Croatia where jumping in front of car or train and suicide with firearms and explosive were more often. Also, in the Mediterranean area of Croatia suicides was mostly committed on open spaces and public places while in continental area of Croatia suicides was mostly committed in private plot.

A review of the psychoneuroimmunologic concepts on the etiology of depressive disorders.

The brain is no longer considered an immunoprivileged organ which is completely separated from the circulating immune cells by the blood-brain barrier and which shows a lowered or changed immunoreactivity. It has become clear that there are numerous interactions between the neurological, immune and neuroendocrinologic systems. The psychiatric disorder which is supposed to be connected to changes in the functioning of the immune system is depression. One of the hypotheses suggesting the pathophysiology of depression is the cytokine hypothesis of depression. According to it, the behavior changes in depressed patients are a consequence of changes in cytokines. Physiological and psychological effects of the immune activation during an infection, primarily mediated by central activity of peripherally excreted proinflammatory cytokines, are called "sickness behavior". Depression is connected with the activation of the inflammatory response system. When it comes to the immune characteristics of depressive disorders, it should be stressed that depression is a heterogeneous disorder, so different types of depression can differ not only psychopathologically but also at the immune level. Depression is characterized by disorders in noradrenergic and serotonergic neurotransmission. Proinflammatory cytokines are included in the noradrenergic and serotonergic neurotransmission in the brain areas that are thought to be involved in the pathogenesis of depression. According to this model, depression can be considered a psychoneuroimmune disease in which the peripheral immune activation is responsible (by excreting the inflammatory mediator) for various behavioral, neuroendocrinologic and neurochemical changes connected to the psychiatric condition.

Combination of polymorphic variants in serotonin transporter and monoamine oxidase-A genes may influence the risk for early-onset alcoholism.

The combinatory effect of polymorphisms in serotonin transporter and monoamine oxidase-A genes on the aetiopathogenesis of alcoholism was investigated in a sample of 714 individuals. Increased frequency of subjects having three 'suspected' genotypes (5-HTTLPR-LL, STin2-1010 and MAO-A 3-repeat allele) was found among type-2 alcoholic patients (P=0.0189). Results highlight serotonergic/genetic contribution to early-onset alcoholism.