World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision.

In this report, which is an update of a guideline published in 2002 (Bandelow et al. 2002, World J Biol Psychiatry 3:171), recommendations for the pharmacological treatment of anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are presented. Since the publication of the first version of this guideline, a substantial number of new randomized controlled studies of anxiolytics have been published. In particular, more relapse prevention studies are now available that show sustained efficacy of anxiolytic drugs. The recommendations, developed by the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-traumatic Stress Disorders, a consensus panel of 30 international experts, are now based on 510 published randomized, placebo- or comparator-controlled clinical studies (RCTs) and 130 open studies and case reports. First-line treatments for these disorders are selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and the calcium channel modulator pregabalin. Tricyclic antidepressants (TCAs) are equally effective for some disorders, but many are less well tolerated than the SSRIs/SNRIs. In treatment-resistant cases, benzodiazepines may be used when the patient does not have a history of substance abuse disorders. Potential treatment options for patients unresponsive to standard treatments are described in this overview. Although these guidelines focus on medications, non-pharmacological were also considered. Cognitive behavioural therapy (CBT) and other variants of behaviour therapy have been sufficiently investigated in controlled studies in patients with anxiety disorders, OCD, and PTSD to support them being recommended either alone or in combination with the above medicines.

Methamphetamine alters expression of DNA methyltransferase 1 mRNA in rat brain.

Methamphetamine, a potent and indirect dopaminergic agonist, also increases glucocorticoid hormone secretion. Glucocorticoid hormones facilitate behavioral effects of methamphetamine in rodents. Several reports suggest that glucocorticoid hormones modulate expression of DNA (cytosine-5-)-methyltransferase 1 (Dnmt1). Dnmt1 was originally recognized as being involved in DNA replication, but a recent study found high levels of Dnmt1 in rodent brains, suggesting a neuron-specific unknown function of Dnmt1. In the present study, we found subchronic methamphetamine treatment (4 mg/kg, i.p., once daily for 21 days) to induce different patterns of Dnmt1 mRNA expression in the nucleus caudatus and nucleus accumbens of two inbred rat strains, Fischer 344/N (increased Dnmt1) and Lewis/N (decreased Dnmt1). These patterns paralleled methamphetamine-induced striatal glucocorticoid receptor mRNA in these two rat strains in our previous study. Because Fischer rats have a hyperresponsive negative feedback in their hypothalamic-pituitary-adrenocortical (HPA) axis and thus a shorter duration corticosterone response to subchronic methamphetamine treatment, they were resistant to sensitizing effects of methamphetamine and their glucocorticoid receptor mRNA levels were upregulated. Lewis rats which have a hyporesponsive feedback in their HPA axis and a longer duration of corticosterone secretion with subchronic methamphetamine were prone to methamphetamine sensitization and their striatal glucocorticoid receptor mRNA levels were downregulated. Our present data suggest that methamphetamine results in differential DNA methylation as well as gene expression in the nucleus caudatus and nucleus accumbens of F344 and Lewis rats. Methamphetamine-induced differences in gene expression might be related to the contrasting susceptibilities of these rats to behavioral and neurochemical effects of methamphetamine.

Renaming schizophrenia: a Japanese perspective.

In order to contribute to reduce the stigma related to schizophrenia and to improve clinical practice in the management of the disorder, the Japanese Society of Psychiatry and Neurology changed in 2002 the old term for the disorder, "Seishin Bunretsu Byo" ("mind-split-disease"), into the new term of "Togo Shitcho Sho" ("integration disorder"). The renaming was triggered by the request of a patients' families group. The main reasons for the renaming were the ambiguity of the old term, the recent advances in schizophrenia research, and the deep-rooted negative image of schizophrenia, in part related to the long-term inhumane treatment of most people with the disorder in the past. The renaming was associated with the shift from the Kraepelinian disease concept to the vulnerability-stress model. A survey carried out seven months after renaming in all prefectures of Japan found that the old term had been replaced by the new one in about 78% of cases. The renaming increased the percentage of cases in which patients were informed of the diagnosis from 36.7% to 69.7% in three years. Eighty-six percent of psychiatrists in the Miyagi prefecture found the new term more suitable to inform patients of the diagnosis as well as to explain the modern concept of the disorder. The Japanese treatment guideline for "Togo Shitcho Sho" was developed in 2004 under the framework of the vulnerability-stress model.

Histamine H1 receptors in schizophrenic patients measured by positron emission tomography.

Increasing evidence has shown that the histaminergic neuron system is implicated in the pathophysiology of schizophrenia. The aim of this study was to compare the distribution of histamine H1 receptors between schizophrenics and normal human subjects in vivo using positron emission tomography (PET). H1 receptor binding was measured in 10 normal subjects and 10 medicated schizophrenic patients by PET and [11C] doxepin, a radioligand for the H1 receptor. The binding potential (BP=Bmax/K(D)) of [11C] doxepin for available brain H1 receptors was calculated by a graphical analysis on voxel-by-voxel basis and compared between schizophrenics and normal subjects using the regions of interest (ROIs) and the statistical parametrical mapping (SPM99). BP values for H1 receptors in the frontal and prefrontal cortices and the cingulate gyrus were significantly lower among the schizophrenic patients than among the control subjects. On the contrary, there were no areas of the brain where H1 receptors were significantly higher among the schizophrenic patients than the control subjects. The results of our study suggest that the central histaminergic neuron system could be involved in the pathophysiology of schizophrenia, although further studies are needed to confirm this hypothesis.

Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain.

Methamphetamine (MAP), the most frequently abused substance in Japan, causes severe drug dependence and psychosis, similar to schizophrenia. It is suggested that long-term alterations in gene expression is related to MAP-induced brain dysfunction, including dependence and psychosis. DNA (cytosine-5) methyltransferase (Dnmt), a methylating enzyme of cytosine residues on CpG-dinucleotides, plays an important role in X chromosome inactivation, genomic imprinting, and gene expression. Reelin is an extracellular matrix protein secreted by GABAergic interneurons. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression replicate the dendritic spine and GABAergic defects described in schizophrenia. DNA methylation plays an important role in the epigenetic modification of reelin expression. We previously found that MAP could alter expression of Dnmt1 mRNA in the rat brain. In this study, we examined the brain mRNA for Dnmt2 and reelin in MAP-treated Wistar rats. Acute MAP (4 mg/kg) treatment significantly decreased Dnmt2 mRNA by 27% to 39% in hippocampus dentate gyrus, CA1, and CA3 24 h after treatment, and significantly decreased reelin mRNA by 28% in frontal cortex 3 h after treatment. These results suggest that (1) MAP can alter DNA methylation as well as expression of genes in these brain regions, and (2) decrease in reelin mRNA in the frontal cortex is similar to heterozygous reeler mice, which might be related to schizophrenia-like psychotic symptoms of MAP psychosis.

Clinical features of sensitization to methamphetamine observed in patients with methamphetamine dependence and psychosis.

Methamphetamine (METH) has been the most popular drug of abuse in Japan for more than 50 years, resulting in serious health and social issues. Most adult abusers in Japan consume only METH; multiple-substance abusers are rare. This unusual aspect of drug abuse makes it possible to observe clearly the sequential alteration of psychiatric symptoms induced by METH without modification by other illegal drugs. Clinical investigation reveals three core characteristics of METH abuse: (1) progressive qualitative alteration in mental symptoms from a nonpsychotic to a prepsychotic to a severely psychotic state; (2) enhanced vulnerability to relapse of psychosis; and (3) very long duration of the vulnerability to relapse. These findings indicate that the phenomenon of sensitization to METH develops during abuse and plays a key role in the susceptibility to and onset of psychosis and in the refractory process. Molecular findings using animal sensitization models may facilitate a better understanding of, and open the way for innovative therapies for, METH psychosis and also chronic schizophrenia.

Electroconvulsive shock increases serotonin transporter in the rat frontal cortex.

The antidepressive action of electroconvulsive shock (ECS) is thought to involve the alteration in serotonin (5-HT) neurotransmission, including the increase in 5-HT release and uptake. In our previous study, 5-HT transporter (5-HTT) mRNA expression was decreased after single and repetitive ECS in rat raphe nucleus. In the present study, we investigated the effects of single and repetitive ECS on the protein levels of 5-HTT in the frontal cortex, hippocampus and raphe nucleus of rat brain using quantitative Western blot analysis. Single ECS did not alter 5-HTT protein expression in any brain regions examined. Repetitive ECS stably increased 5-HTT protein in the frontal cortex, but not in the hippocampus and raphe nucleus. Because ECS is known to facilitate the release of neurotransmitters, our results suggest that the increased 5-HTT protein expression in the frontal cortex might be a compensatory change against the enhanced 5-HT release by ECS in presynaptic terminals.

Changes in regional cerebral blood flow abnormalities in late-life depression following response to electroconvulsive therapy.

The impact of electroconvulsive therapy (ECT) on the regional cerebral blood flow (rCBF) abnormalities in late-life depression is still unknown and the clinical significance of these findings in late-life depression has not been fully discussed. Using single photon emission computed tomography (SPECT) with 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO), we examined the changes of rCBF patterns in nine late-life patients with major depressive episodes before and following response to ECT compared with nine age- and sex-matched healthy volunteers. Statistical comparisons were made on both region-of-interest (ROI) and voxel-by-voxel bases. In ROI-based analyses, a mean rCBF was significantly decreased in the patients before ECT compared with the control, significantly increased (normalized) in the patients 2 weeks after ECT compared with that before ECT, and still increased in the patients 12 weeks after ECT compared with that before ECT. In voxel-by-voxel analyses, a significant rCBF reduction was found in the bilateral pre- and subcallosal anterior cingulate cortex, the bilateral caudal orbitofrontal cortex, the right insular cortex and the right posterior middle frontal gyrus in patients before ECT compared with the control, and similar rCBF patterns were shown at 2 weeks and 12 weeks after ECT. We propose the hypothesis that a mean rCBF reduction may have a state-related property while persistent anterior paralimbic hypoperfusion may have a trait-like property, which relates to the relapse vulnerability as well as a tendency toward medication failure and illness chronicity in late-life depression.

The long-term course of seizure susceptibility in two patients with juvenile myoclonic epilepsy.

We have observed epileptic seizures of juvenile myoclonic epilepsy (JME) to be surprisingly sensitive to higher mental activity. The purpose of the present study was to examine changes over time in seizure susceptibility in two patients with JME who we followed-up for over 20 years. During the period, they were repeatedly subjected to provocative cognitive tasking, that is, to 'neuropsychological EEG activation'. Tasks included reading, speaking, writing, written arithmetic, mental calculation, and spatial construction. During the first 15 years after the onset of symptoms, higher mental activities, mainly associated with use of the hands, i.e. writing, written calculation, and spatial construction, as well as physiological factors, such as sleep deprivation, awakening, and fatigue, precipitated the seizures. Generalized tonic-clonic and absence seizures but not myoclonic seizures disappeared almost completely after antiepileptic treatment. After age 30, the provocative effect of higher mental activities persisted, and the myoclonic seizures decreased under same drug regimen. These observations suggest that the pathophysiology of JME improves with time but persists for a long time, and that it is closely related to a neural network involved in higher mental activities mainly associated with use of the hands rather than in physiological factors emphasized in prior reports.