The connection of temperament with ADHD occurrence and persistence into adulthood - An investigation in 18 year old males.

BACKGROUND: This study intended to determine whether certain traits of temperament are associated with former and current ADHD symptomatology in a non-clinical sample of 18 year old males. METHODS: We performed a cross sectional descriptive study of 3280 men during the examination for military service. The investigation included a socio-demographic questionnaire, screening for substance abuse, temperament (TEMPS-M), past (WURS) and current (ADHD symptom checklist) ADHD symptomatology. RESULTS: We found a correlation of cyclothymic (p<.001), irritable (p<.001) and anxious (p<.05) temperament with occurrence and severity of past and present ADHD symptomatology. No significant correlation has been detected for hyperthymic and depressive temperament. Judged retrospectively, ADHD symptoms were strongly consistent over time. LIMITATIONS: The sample consists of men only. These had to be fit enough to be enlisted for military service; men with severe mental or physical disorders were thus excluded. Furthermore, the cross-sectional study design does not allow making conclusions about the temporal relationships between ADHD symptoms and substance misuse. CONCLUSIONS: These results indicate that a temperament based approach towards those affected by ADHD might be useful. Subtyping ADHD by integrating temperament profiles in diagnosis and treatment of the disorder could help explain some of the heterogeneity of the disease.

Association of short-term response to haloperidol treatment with a polymorphism in the dopamine D(2) receptor gene.

OBJECTIVE: Pharmacogenetic influences on therapeutic response to neuroleptic treatment are poorly understood. This study investigates the association of response to short-term haloperidol treatment with a Taq I polymorphism in the DRD2 gene. METHOD: Fifty-seven patients with acute psychosis were treated with haloperidol for up to 28 days. Improvement and response were measured by using the Positive and Negative Syndrome SCALE: Forty-one patients were homozygous for allele 2, and 16 were heterozygous. RESULTS: Heterozygous patients showed a greater improvement in positive, but not in negative, symptoms on all treatment days than patients homozygous for allele 2. Differences in improvement of positive symptoms reached statistical significance on days 14, 21, and 28. On treatment day 14, 10 (62.5%) of 16 heterozygous patients had at least 50% improvement of positive symptoms, compared with 11 (28.9%) of 38 homozygous patients. CONCLUSIONS: These results support the hypothesis that genetic variations in the DRD2 gene may influence the individual response to antipsychotics.

Tiagabine appears not to be efficacious in the treatment of acute mania.

BACKGROUND: Because a GABAergic hypofunction has been implied in the pathophysiology of mania, we have tested the antimanic properties of the GABA transporter 1 inhibitor tiagabine. METHOD: An open trial was conducted in 8 acutely manic inpatients with DSM-IV bipolar I disorder, 2 of them with tiagabine monotherapy and 6 with tiagabine as an add-on to previously insufficient mood-stabilizing medication. The study duration was 14 days. Changes in psychopathology were assessed by the Bech-Rafaelsen Mania Rating Scale. RESULTS: None of the patients showed clear-cut relief from manic symptoms during the 2-week observation period. In 2 patients, we saw pronounced side effects (nausea and vomiting in one and a generalized tonic-clonic seizure in the other). CONCLUSION: The results from this open trial suggest that tiagabine seems to have no pronounced antimanic efficacy compared with standard treatments such as valproate, lithium, or neuroleptics. It also appears that rapid dosage increases for antimanic treatment can cause potentially severe side effects.

Tolerability of long term clozapine treatment.

Tolerability of long term clozapine treatment (7-8 years) was investigated in 27 female patients (age 34-77 years). Diagnosis according to ICD 9 was schizophrenia in 21 patients, severe psychomotor agitation with mental deficiency in 4 patients and an "endogenous" depression in 2 patients. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The duration of the disorder was 10-36 years, duration of hospitalisation 10-36 years. At the day of investigation the total dose of clozapine ranged from 52-826 g, the average total dose being 385 g. The daily dose of clozapine ranged from 75 to 600 mg, the average daily dose being 225 mg. Only 2 patients were treated exclusively with clozapine, the other 25 patients were also receiving other neuroleptics. Seventy eight per cent of the investigated patients complained about hypersalivation and 63% showed overweight. In 37% of the patients the EEG demonstrated abnormalities. Mild parkinsonism was reported in 15% and akathisia in 11% of the patients, all these patients being on combined treatment. Clozapine did not induce tardive dysakinesia (TD) in any of the patients within a treatment period of 7-8 years. It is concluded that a potential benefit of clozapine includes a low incidence of neurological side effects even after long term administration.

Phospholipid and phospholipid metabolites in rat frontal cortex are decreased following nucleus basalis lesions.

Membrane phospholipid metabolism is abnormal in Alzheimer's disease (AD) brain. Phosphatidylcholine and phosphatidylethanolamine levels are decreased as are choline and ethanolamine, while glycerophosphocholine (GPC) and glycerophosphoethanolamine are increased. To develop a rat model for these changes, we examined the effects of unilateral lesion of the cholinergic nucleus basalis (nBM) with ibotenic acid (10 mg/ml in PBS, 0.5 microliter) and sham lesion on frontocortical phospholipid, choline and GPC. After one week, choline acetyltransferase activity in frontal cortex was decreased (26%, p < 0.005, n = 14) on the nBM ibotenate-lesion side relative to the contralateral side, while there were no differences following the nBM sham-lesion. Levels of membrane phospholipids (nmol/mg protein) in adjacent frontal cortex sections exhibited concomitant decreases (13%, p < 0.05, n = 14) on the nBM ibotenate-lesion side, while there were no differences following the nBM sham-lesion. Tissue nBM ibotenate-lesion frontocortical choline and GPC levels were also decreased relative to those in control tissue (choline: 21%, p < 0.05, n = 14; GPC: 10%, p < 0.05, n = 14), while nBM sham-lesion showed no effect. Muscarinic receptor sensitivity in frontal cortex following nBM ibotenate-lesion was increased, as measured by carbachol-stimulated inositol phosphate production (p < 0.001, n = 12), indicating that increased receptor mediated phospholipid hydrolysis in cortex may occur following nBM ibotenate-lesion. These data suggest that impaired cholinergic transmission alters phospholipid metabolism in cholinergic target regions.

An open label study of gabapentin in the treatment of acute mania.

Recent anecdotal single case reports have suggested that the new antiepileptic drug gabapentin might be effective in the treatment of manic episodes and in the prophylaxis of bipolar disorder. In the present open trial, 14 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Six patients were treated with gabapentin as add-on medication and 8 patients were treated with a high dose of gabapentin alone. Gabapentin was both efficacious and safe when applied in combination with other drugs such as lithium and valproic acid. All patients in the add-on group and 4/8 patients on gabapentin monotherapy finished the 21 day protocol. Analysis of the scores of the Bech-Rafaelsen Mania Assessment Scale (BRMAS) of these patients showed that the mean BRMAS score declined from 37.7 to 7.8 on day 21 in the add-on group and from 27.8 to 9.0 in 4/8 patients finishing 21 days in the monotherapy group. It is suggested that gabapentin monotherapy might be useful in selected patients to treat modest but not severe manic states. In addition, gabapentin in conjunction with other effective mood stabilisers seems to be safe and efficacious in the treatment of severe mania.

Heterogeneity of binding sites for N-ethylcarboxamido[3H]adenosine in rat brain: effects of N-ethylmaleimide.

Binding sites for N-ethylcarboxamido[3H]adenosine (NECA) in rat brain membranes and cryostat sections were examined in relation to their sensitivities to displacement by unlabeled NECA and R(-)-phenylisopropyladenosine (R-PIA). In membrane fractions from cerebral cortex, cerebellum, hippocampus and striatum, nanomolar concentrations of these adenosine receptor agonists displaced [3H]NECA such that R-PIA was more effective than NECA, consistent with the presence of an A1-adenosine receptor. At concentrations of displacing agent higher than 1 microM, R-PIA was unable to displace [3H]NECA further in cerebral cortex, cerebellum and hippocampus. In striatum, a second R-PIA-sensitive component of [3H]NECA binding was evident which was more sensitive to NECA than to R-PIA, i.e. it showed the characteristics of an A2-adenosine receptor. In striatum, however, R-PIA was also unable to displace [3H]NECA binding completely. Similar results were obtained in quantitative autoradiographic studies. Preincubation of cryostat sections with N-ethylmaleimide (NEM) abolished both the A1- and R-PIA-insensitive binding components such that both NECA and R-PIA were able to displace [3H]NECA binding completely. The remaining sites showed IC50 values of 0.13 and 3.68 microM for NECA and R-PIA, respectively. These A2-like [3H]NECA binding sites had a highly specific distribution in the brain, being concentrated in the striatum, nucleus accumbens and olfactory tubercle. The results indicate the presence in brain tissue of at least 3 classes of [3H]NECA binding sites, an A1-site, an A2-site and a third, unidentified R-PIA-insensitive site.

Effects of subchronic pretreatment with D-fenfluramine or p-chloroamphetamine on [3H]inositolmonophosphate accumulation in rat cortical miniprisms.

Phosphatidylinositol (PI) breakdown in rat cerebral cortex is stimulated by serotonin (5-HT), acting via 5-HT2 and possibly 5-HT3 receptors and by acetylcholine or carbachol, acting via muscarinic M1 and M3 receptors. Serotoninergic neurons have been described as tonically inhibiting cortical acetylcholine release. We studied the effects of subchronic pretreatment with high doses of D-fenfluramine (10 mg/kg, i.p., daily for 4 days), which releases 5-HT and blocks its reuptake, on 5-HT-and carbachol-stimulated PI breakdown, as measured by [3H]inositolmonophosphate ([3H]IP1) accumulation in cortical miniprisms. This pretreatment decreased 5-HT-stimulated [3H]IP1 accumulation, suggesting that a prolonged increase of 5-HT in the synaptic cleft reduces the activity of the transducing system used by postsynaptic 5-HT receptors. Carbachol-stimulated PI breakdown was unaltered by pretreatment with D-fenfluramine. Pretreatment with a single dose of p-chloroamphetamine (5 mg/kg), a serotoninergic neurotoxin, which depleted cortical 5-HT by 85%, did not change [3H]IP1 accumulation after stimulation by 5-HT or by the muscarinic agonist carbachol. Subchronic pretreatment, which depleted cortical 5-HT by 90%, decreased both 5-HT- and carbachol-stimulated [3H]IP1 accumulation. The mechanism by which p-chloroamphetamine, but not D-fenfluramine, diminishes the PI response to carbachol might involve impairment of the tonic serotoninergic inhibition of acetylcholine release.

Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs.

We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

Properties of binding sites for [3H]cyclohexyladenosine in the hippocampus and other regions of rat brain: a quantitative autoradiographic study.

The properties of binding sites for the adenosine receptor ligand, [3H]cyclohexyladenosine ([3H]CHA), were investigated in rat brain using quantitative autoradiography. Scatchard analysis of the binding data showed that there were no significant differences between Kd values for [3H]CHA in any of the regions investigated. The highest concentrations of [3H]CHA binding sites were found in the cerebellum (molecular layer) and the stratum oriens and stratum radiatum of the hippocampus (CAI region). Displacement curves obtained using N-ethylcarboxamidoadenosine (NECA) and the R- and S-diastereoisomers of phenylisopropyl adenosine (PIA) showed the [3H]CHA binding sites to have the pharmacological properties of A1-adenosine receptors, i.e. the order of potency for these derivatives was R-PIA greater than NECA greater than S-PIA, in all regions tested. Further, [3H]CHA binding was in all cases attenuated by the guanosine triphosphate derivative, beta, gamma-imidoguanosine triphosphate. These results indicate that [3H]CHA binding sites throughout the central nervous system have the properties of A1-adenosine receptors and that these are in all regions associated with guanine nucleotide regulatory proteins.

Effects of unilateral lesion of the nucleus basalis magnocellularis on carbachol- and serotonin-stimulated [3H]inositolmonophosphate accumulation in rat fronto-parietal cortex.

We examined the effects of ibotenic acid induced unilateral lesion of the nucleus basalis magnocellularis (nBM) on carbachol- and serotonin-stimulated phosphoinositide (PI) breakdown in miniprisms obtained from rat fronto-parietal cortex 1 week following the lesion. Lesion-side muscarinic and serotoninergic receptor responsivity to agonist increased linearly relative to the severity of the nBM lesion as measured by choline acetyltransferase (ChAT) activity. These results provide further evidence for an interaction between central cholinergic and serotoninergic neurons.

New perspectives in the treatment of acute mania: a single case report.

1. There is increasing evidence that standard treatment of mania with lithium or neuroleptics fails in many subtypes of mania, e.g. dysphoric mania or rapid cycling, and new strategies are needed. 2. This single case report reports on possibilities and pitfalls in alternative attempts to tackle a severe manic syndrome successfully. 3. In this patient, lamotrigine and valproate, the latter only in an i.v. formulation, led to a relief from mania. 4. It is concluded that the success of this treatment may be due to a common underlying mechanism of action of these drugs, most likely on the level of ion channel regulation, and that further experience with alternative formulations of standard treatments such as valproate i.v. should be collected.

Sensitive measurement of agonist-stimulated [3H]inositol monophosphate accumulation in rat cortical miniprisms.

Phosphoinositide (PI) breakdown is an important transmembrane signaling mechanism in rat brain and numerous transmitter receptors are linked to this mechanism. Since agonist-stimulated PI breakdown is often changed after drug pretreatment, assessment of changes in PI breakdown represents an important tool in drug development. PI breakdown is commonly monitored by assaying [3H]inositol monophosphate ([3H]IP1) accumulation in the presence of lithium as an inhibitor of inositol monophosphatase. The present protocol presents a lithium-inhibited [3H]IP1 accumulation assay that enhances relatively weak agonist-stimulated [3H]IP1 accumulation signals by thorough oxygenation during agonist stimulation. The protocol is particularly useful in the measurement of [3H]IP1 accumulation after in vitro exposure to relatively weak stimulants, such as serotonin (5-HT), and/or after animal pretreatments that decrease the response to the agonist. In the case of 5-HT stimulation the monoamine oxidase (MAO) inhibitor, tranylcypromine, was added to the incubation medium to inhibit breakdown of exogenous serotonin. We used this protocol to measure 5-HT- and carbachol-stimulated [3H]IP1 accumulation in cortical miniprisms obtained from rats pretreated with D-fenfluramine. D-Fenfluramine is a drug that acutely releases 5-HT into the synaptic cleft and blocks its reuptake.

Trimipramine fails to exert antimanic efficacy: a case of the discrepancy between in vitro rationale and clinical efficacy.

Standard mood stabilizers, such as lithium and haloperidol, and anticonvulsants show effectiveness in a maximum of 60%-70% of acutely manic patients. Obviously, there is a clinical need to evaluate other treatment options. Current pathophysiologic concepts suggest that substances with an ameliorating effect on dopaminergic hyperfunction, serotonergic hypofunction, or GABAergic hypofunction might be useful, as may be substances with calcium-antagonistic effects. In vitro, the antidepressant trimipramine exerts dopamine- and calcium-antagonistic properties. Therefore, we conducted an open trial to screen it for antimanic action. We found no clinical benefit in four acutely manic patients receiving up to 400 mg/d of trimipramine. It is concluded that, at least in the case of trimipramine, the pharmacologic profile is not helpful in predicting potential effectiveness in mania.

Screening questionnaires in the detection of hazardous alcohol consumption in the general hospital: direct or disguised assessment?

OBJECTIVE: The aim of this study was to compare the validity of two direct screening questionnaires, the CAGE and MAST, in the detection of hazardous alcohol consumption with a disguised assessment by using the Trauma Scale in a poststratified general hospital sample. METHOD: Surgical and medical inpatients (N = 1,379) completed the three questionnaires. Hazardous alcohol consumption was defined by criteria derived from a World Health Organization study and assessed using self-reported quantity and frequency. RESULTS: The sensitivity of the Trauma Scale was not significantly different compared to the CAGE and MAST, whereas the direct questionnaires were higher in specificity and overall accuracy (p < .0001). In male surgical patients the detection rate of the Trauma Scale was higher compared to the CAGE (p < .05). Thirteen percent of subjects with hazardous levels of alcohol consumption were detected by the Trauma Scale only. In female surgical patients, the Trauma Scale, when used as an additional tool, does not improve the detection of hazardous drinkers. CONCLUSIONS: Because of the low specificity, indirect assessment using a history of trauma cannot be recommended as a screening instrument in a general hospital setting. Despite a high number of false positives, the Trauma Scale may serve as an additional tool in conjunction with direct questionnaires when high sensitivity is desired.

Lesch typology and temperament in opioid dependence: a cross-sectional study.

AIMS: The first aim of this study is to investigate the impact of different temperaments in opiate dependency patients. The second aim of this study is to define therapy relevant subgroups in opiate addiction for further basic clinical research and therapy. METHODS: In the time period from September to November 2010, 101 patients (72 males and 29 females) which fulfilled the diagnosis of opiate dependency according to DSM-IV-TR were recruited consecutively. All patients were in treatment at the Oum El Nour rehabilitation center/Lebanon (Inpatient and Outpatient groups). Lesch Alcoholism Typology modified for assessment of opiate addicts, and the briefTEMPS-M, Arabic version were used. RESULTS: The organic Type IV group was the most prevalent (48.5%) among the sample followed by the Affective Type III group (41.6%) and the minority represented the two other types (I & II). The organic Type IV group represented the major type in the cyclothymic and anxious temperament. In the contrary the other two groups (I & II) were the minority among the cyclothymics.

Suicidal ideation and temperament: an investigation among college students.

BACKGROUND: Suicide is a major health problem accounting for up to 1.5 percent of all deaths worldwide and represents one of the most common causes of death in adolescents and young adults. A number of studies has been performed to establish risk factors for suicide in patients with psychiatric disorders including temperamental features. This study set out to assess the relationship between suicidal ideation and temperament in young adults. METHODS: A cross-sectional sample of healthy college students (n=1381) was examined using a self-rating questionnaire. Suicidal ideation, social background, educational status, substance abuse, and affective temperament according to TEMPS-M were assessed. Predictors of lifetime suicidal ideation were examined in multivariate logistic regression analyses. RESULTS: Suicidal ideation was reported by 12.5% of all subjects at some point in their life and was higher in nicotine dependents, youth with alcohol related problems and users of illicit substances as well as in youth with lower educational status. Lifetime suicidal ideation was associated with the anxious, depressive and cyclothymic temperament in both sexes and the irritable temperament in males. These results remained significant after adjustment for smoking status, frequency of alcohol consumption, drug experience and educational status in a multivariate logistic regression analysis. LIMITATIONS: The use of self-rating instruments always reduces objectivity and introduces the possibility of misreporting. CONCLUSIONS: Considering the fact that many subjects completing suicide have never been diagnosed with mental disorders it might be reasonable to include an investigation of temperament in screenings for risk of suicide. This might be especially useful for health care professionals without mental health care background.

Inpatient treatment of major depression in Austria between 1989 and 2009: impact of downsizing of psychiatric hospitals on admissions, suicide rates and outpatient psychiatric services.

BACKGROUND: During the last 20 years Austrian psychiatric services underwent fundamental changes, as a focus was set on downsizing psychiatric hospitals. Little is known about how restructuring of mental health services affected patients with major depression and suicide rates. METHODS: Monthly hospital discharges from all hospitals in Austria with the diagnosis of unipolar major depression as primary reason for inpatient treatment were obtained for the time period between 1989 and 2008. These data were correlated with relevant parameters from the general health system, such as number of hospital beds, suicide rate, density of psychotherapists and sales of antidepressants. RESULTS: While the number of psychiatric beds was reduced by almost 30%, the total annual numbers of inpatient treatment episodes for depression increased by 360%. This increase was stronger for men than for women. Further on this development was accompanied by a decrease in the suicide rate and an improvement in the availability of professional outpatient mental health service providers. LIMITATIONS: Only aggregated patient data and no single case histories were available for this study. The validity of the correct diagnosis of unipolar major depression must be doubted, as most likely not all patients were seen by a clinical expert. CONCLUSIONS: Our data show that although inpatient treatment for unipolar major depression dramatically increased, reduction of psychiatric beds did not lead to an increase of suicide rates.

The impact of temperament in the course of alcohol dependence.

AIMS: The aim of this study was to assess the impact of temperamental traits in alcohol dependent patients on the course of illness. METHODS: The case files of 116 alcohol dependent patients, according to ICD-10 and DSM-IV-TR, were examined retrospectively. All patients were in treatment between 02/08 and 03/09 at the Psychiatric Department of the General Hospital Vienna, either at the alcohol outpatient clinic or the psychiatric ward, which has the treatment focus on alcohol dependence. The brief TEMPS-M auto-questionnaire was used to assess the temperamental distribution. The dimensions of alcohol dependence have been assessed using the Lesch Alcoholism Typology, a computerized structured interview. The potential effect of temperamental scores on various outcomes describing the course of illness is investigated using multi-variable regression models. RESULTS: Cyclothymic score was the only temperament which significantly influenced the age of onset of alcohol abuse and age of onset of alcohol dependence. Backward selection among temperaments exhibits depressive temperament as most important effect regarding the likelihood of suicide-attempts in the patient's case history and anxious temperament as most important effect regarding having psychiatric treatment focusing on alcohol dependence prior to current in- or outpatient stay. LIMITATIONS: The sample size of this study is small compared to the number of investigated outcomes and temperaments. Further, a healthy control group, matched for age and gender, was not available for comparison of the temperament sub-scores. CONCLUSION: Dominant cyclothymic, but also depressive and anxious temperament, seem to be negative predictors for the course of illness in alcohol dependence. Regarding positive long term outcome specific evidence based medical treatment approaches are needed for these patients.