Keisuke Motomura

Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis

BACKGROUND Lithium is the established standard in the long-term treatment of bipolar disorder, but several new drugs have been assessed for this indication. We did a network meta-analysis to investigate the comparative efficacy and tolerability of available pharmacological treatment strategies for bipolar disorder. METHODS We systematically searched Embase, Medline, PreMedline, PsycINFO, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published before June 28, 2013, that compared active treatments for bipolar disorder (or placebo), either as monotherapy or as add-on treatment, for at least 12 weeks. The primary outcomes were the number of participants with recurrence of any mood episode, and the number of participants who discontinued the trial because of adverse events. We assessed efficacy and tolerability of bipolar treatments using a random-effects network meta-analysis within a Bayesian framework. FINDINGS We screened 114 potentially eligible studies and identified 33 randomised controlled trials, published between 1970 and 2012, that examined 17 treatments for bipolar disorder (or placebo) in 6846 participants. Participants assigned to all assessed treatments had a significantly lower risk of any mood relapse or recurrence compared with placebo, except for those assigned to aripiprazole (risk ratio [RR] 0·62, 95% credible interval [CrI] 0·38-1·03), carbamazepine (RR 0·68, 0·44-1·06), imipramine (RR 0·95, 0·66-1·36), and paliperidone (RR 0·84, 0·56-1·24). Lamotrigine and placebo were significantly better tolerated than carbamazepine (lamotrigine, RR 5·24, 1·07-26·32; placebo, RR 3·60, 1·04-12·94), lithium (RR 3·76, 1·13-12·66; RR 2·58, 1·33-5·39), or lithium plus valproate (RR 5·95, 1·02-33·33; RR 4·09, 1·01-16·96). INTERPRETATION Although most of the drugs analysed were more efficacious than placebo and generally well tolerated, differences in the quality of evidence and the side-effect profiles should be taken into consideration by clinicians and patients. In view of the efficacy in prevention of both manic episode and depressive episode relapse or recurrence and the better quality of the supporting evidence, lithium should remain the first-line treatment when prescribing a relapse-prevention drug in patients with bipolar disorder, notwithstanding its tolerability profile. FUNDING None.

Effects of behavior therapy on regional cerebral blood flow in obsessive–compulsive disorder

Very few functional neuroimaging studies have been performed on patients with obsessive-compulsive disorder (OCD) undergoing behavior therapy, even though it is recognized to be an effective treatment for this disorder. We measured the regional cerebral blood flow (rCBF) using the Xenon inhalation method in 31 treatment-refractory patients with OCD and the same number of age-matched normal controls. We also studied changes in rCBF in 22 OCD patients who had demonstrated a significant improvement after the behavior therapy. The OCD patients showed a significant bilateral elevation in the rCBF in the basal ganglia compared with the normal controls. After successful treatment, a significant decrease was found in the rCBF in the right head of the caudate nucleus that tended to correlate with clinical improvement.

Effect of atypical antipsychotics on phencyclidine-induced expression of arc in rat brain

The effect of atypical antipsychotics on the immediate-early gene, arc (activity-regulated cytoskeleton-associated gene), expression was investigated in phencyclidine (PCP)-treated rats using RT-PCR. Administration of PCP (10 mg/kg) increased arc mRNA levels in the prefrontal cortex, nucleus accumbens and posterior cingulate cortex. Pretreatment with clozapine (20 mg/kg), olanzapine (10 mg/kg) and risperidone (2 mg/kg), but not haloperidol (2 mg/kg), prevented PCP-induced arc expression in the prefrontal cortex and nucleus accumbens. Pretreatment of haloperidol increased the striatal arc mRNA levels. Clozapine, olanzapine and haloperidol inhibited the PCP-induced arc expression in the posterior cingulate cortex. These results suggest that the effects of antipsychotic drugs on PCP-induced arc expression in the prefrontal cortex and nucleus accumbens are useful for distinguishing atypical antipsychotic properties of the drugs.

Effect of acute imipramine administration on the pattern of forced swim-induced c-Fos expression in the mouse brain

The forced swim test (FST) has been widely used for the preclinical evaluation of antidepressant drugs. Despite considerable differences in the protocol, equivalence of the FST for rats and mice has been rarely questioned. Previous research on the FST for rats revealed that repeated administration of antidepressant drugs attenuates the c-Fos response to swim stress in the hypothalamus and limbic regions. However, few studies have made similar investigations using the FST for mice. In the present study, we explored the mouse brain through immunohistochemistry staining for c-Fos after acute administration of imipramine or saline with or without a subsequent swim session. Imipramine enhanced the c-Fos density in regions of the central extended amygdala, while forced swim stress increased c-Fos expression in some hypothalamic (the ventrolateral preoptic nucleus and dorsomedial nucleus) and brain stem regions, which is consistent with previous reports. In contrast to previous literature with rats, swim stress brought a significant increase in c-Fos expression in the lateral septal nucleus and some other regions in the hypothalamus (the intermediate hypothalamic area, the paraventricular and arcuate nucleus) only in the imipramine-pretreated group, which has not been observed previously. In the arcuate nucleus, double immunostaining revealed that c-Fos was rarely co-expressed with proopiomelanocortin or tyrosine hydroxylase regardless of imipramine treatment. The present results suggest that the activation of several regions in the lateral septum and the hypothalamus underlies antidepressant-like effect in the mouse FST.

Neurocognitive profile of euthymic Japanese patients with bipolar disorder

Neurocognitive impairment is one of the core symptoms of bipolar disorder (BD). The MATRICS Cognitive Consensus Battery (MCCB) is a potential consensus assessment tool to evaluate cognitive function in patients with BD. Here, we report on cognitive deficits evaluated using the MCCB Japanese version (MCCB‐J) in euthymic Japanese patients with BD, and compare them with scores in previous studies.

Current Viewpoints on DSM-5 in Japan

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM‐5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD‐10) to categorize disorders and determine treatment fees. However, since the publication of the DSM‐III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM‐5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM‐5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive–Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance‐Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.

Lost in translation: Confusion about depression and antidepressant therapy in Japan

ANTIDEPRESSANT THERAPY IS now the subject of a nation-wide controversy in Japan. Japanese psychiatrists are being accused of dubious diagnoses, excessive prescriptions and insufficient understanding of personal mentalities. What has happened to us? Japanese psychiatrists had preserved the endogenous–neurotic dichotomy of depression and had regarded intensive pharmacotherapy (with tricyclic antidepressants) as treatment for endogenous depression until around the turn of the century when selective serotonin re-uptake inhibitors were introduced to Japan. We then came to know that effects of newer antidepressants were established through randomized controlled trials that recruited patients with major depression. Thereafter, results of numerous clinical trials were introduced and the language of the psychiatrist changed drastically, while we hardly grasped the gestalt of major depression. Is this a problem inherent in the concept of the disease, or have we failed to import anything attached to it? Apart from the cultural context, here we try to analyze what in the concept of major depression confuses us. When major depressive disorder appeared in the Research Diagnostic Criteria, it was described as a category encompassing patients of various subtypes, including ‘some cases that would be categorized as neurotic depression, and virtually all that would be classified as involutional depression, psychotic depression, and manic depressive illness, depressed type.’ Although several subtypes of depressive disorder were provided, the concept of major depression seemed to reject a clear-cut separation of these types. Such criticism of the classification of depression was developed by British psychiatrists early in the last century through meticulous clinical observation, and it is still echoed in several recent epidemiological studies that demonstrate the entangled effects of environmental and genetic factors on the onset of major depression. Empirically, we appreciate the importance of this critical attitude toward simplistic attribution; the more closely a patient is studied, the harder it becomes to justify simple qualitative distinctions. Detailed knowledge about the environmental and constitutional factors of each patient is crucial for treatment. For example, a patient who shows a seemingly reactive onset may actually have considerable genetic risk, whereas another patient with endogenomorphic features may be affected by an unstable relationship with his or her spouse. When we disentangle the threads, we have to draw them one after another. Similarly, for each patient, effective treatment (whether it is pharmacotherapy, cognitive modification or assistance with realistic problem solutions) may vary at each stage. However, the effectiveness of such personalized methods of treatment is difficult to demonstrate in clinical trials. The evidence level in the treatment of such a heterogeneous disease may reflect methodological difficulties rather than actual importance in clinical practice. Most clinical trials recruit numerous patients with major depression irrespective of such diversity, resulting in generalizable findings with modest significance. When clinicians other than the specialists are informed of these results, they understand only the generalizable relationship between major depression and its treatment response. The critical attitude toward simplification, which established the concept of the disease, is virtually lost, and there remains only a broad category that is susceptible to medicalization. Ironically, what was once a criticism of simplification now serves as the grounds for further simplification. Recognizing this process may be helpful in analyzing the ongoing conflict over bereavement exclusion criteria. While Kendler argues for the elimination of the criteria relying on the prudence of ‘good’ psychiatrists, Horwitz and Wakefield address the potential harm of over-diagnosing depressive disorders by general physicians in the primary-care setting who have been informed about simplified concepts Psychiatry and Clinical Neurosciences 2013; 67: 1–2 doi:10.1111/pcn.12011

Medioventral part of the posterior thalamus in the mouse.

The posterior thalamus (Po) consists of heterogeneous groups of cells, which have not been clearly defined. In the present study, we focused on a part of the Po in the mouse brain, which is located caudally to the ventral posterior nucleus and rostromedially to the medial geniculate nucleus and shows distinct calretinin immunoreactivity. While we found the region had a considerable unity on the cytoarchitectural and histochemical grounds, it did not correspond to any particular nucleus but partially involved three structures in a widely used brain atlas (Franklin and Paxinos, 2008). Therefore, we tentatively designated the region as the medioventral part of the posterior thalamus (PoMV) and examined its anatomical features with immunohistochemistry and retrograde tract-tracing. The PoMV was appreciated as a reticular structure with prominent calretinin immunoreactivity, especially in horizontal sections, and displayed apparent differences in the cytoarchitecture from its surrounding regions. The PoMV had two divisions: the dorsal division (PoMVd), which contained parvalbuminimmunoreactive fibers, and the ventral division (PoMVv), which lacked these fibers. The tract-tracing studies showed that the somata retrogradely labeled from the injections in the insular cortex and some of the extended amygdalar regions were fairly concentrated within the PoMV, especially in the PoMVd. On the other hand, the labeling from the medial hypothalamus injections was found predominantly within the PoMVv. These findings indicate that the PoMV can be regarded as a distinct structure within the Po, and it may play a role in the emotional aspect of somatosensory processing.

Pattern of c-Fos expression induced by tail suspension test in the mouse brain

The tail suspension test (TST) has been widely used as a screening assay for antidepressant drugs. However, the neural substrates underlying the stress response and antidepressant-like effect during the TST remain largely unknown despite the prevalence of this test. In the present study, we used immunohistochemistry to examine alterations in c-Fos expression as a measure of neuronal activity in the mouse brain after acute administration of the antidepressant drugs nortriptyline or escitalopram (or saline as a control) with or without a subsequent TST session. We found that without the TST session, nortriptyline administration enhanced the density of c-Fos-immunoreactive cells in regions of the central extended amygdala, paraventricular hypothalamic nucleus, and relevant regions of the brain stem, whereas escitalopram did not change c-Fos expression in any region. Following the TST in the absence of antidepressant drugs, we observed a significant increase in c-Fos-positive cell density in a number of brain regions within the limbic telencephalon, hypothalamus, and brain stem. We detected a statistically significant interaction using an analysis of variance between the main effects of the drug and stress response in four regions: the infralimbic cortex, lateral septal nucleus (intermediate part), ventrolateral preoptic nucleus, and solitary nucleus. Following the TST, escitalopram but not nortriptyline increased c-Fos-positive cell density in the infralimbic cortex and ventrolateral preoptic nucleus, whereas nortriptyline but not escitalopram increased c-Fos expression in the solitary nucleus. Both antidepressants significantly increased c-Fos expression in the lateral septal nucleus (intermediate part). The present results indicate that neuronal activity increases in septo-hypothalamic regions and related structures, especially the lateral septal nucleus, following administration of drugs producing an antidepressant-like effect in mice subjected to the TST.