Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT(1A) receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT(1A) agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT(1A) agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT(1A) receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia

Dose Reduction/Discontinuation of Antipsychotic Drugs in Psychosis; Effect on Cognition and Functional Outcomes

Backgrounds: There is a debate regarding the optimal timing of discontinuation of antipsychotic drugs in patients with first episode psychosis (FEP) or schizophrenia. We aimed to provide a review of the literature on which strategy (medication maintenance vs. dose reduction/discontinuation) is more likely to maximize outcomes, such as cognition and social function.Methods: Using PubMed, the Cochrane Library and systematic reviews, articles published between 2007 and 2018 were reviewed, which investigated the effect of dose reduction/discontinuation vs. maintenance treatment on measures of cognition and/or social function in FEP and schizophrenia.Results: Six studies were identified; 2 studies reported on cognition while 4 studies concern social function. All studies except one reported that improvement of functional outcomes in remitted patients with FEP or schizophrenia allocated to a dose reduction/discontinuation arm was equal to or better than that in patients for whom medication doses were maintained. One trial of social function with a 1-year follow-up period found a greater improvement in the medication maintenance group, while no group difference was observed with 3-year and 10-year follow-up periods. On the other hand, a 7-year follow-up study found a superiority for the dose reduction/discontinuation regimen in terms of social outcome. Two studies on cognition with a short follow-up period reported a greater improvement for the dose reduction/discontinuation group.Conclusions: Information on cognition and social function has been relatively sparse. These measures of functional outcome should be considered in deciding which strategy of antipsychotic treatments is beneficial in individual cases with FEP or schizophrenia

Social Cognitive Impairments as a Target of Non-invasive Brain Stimulation for Functional Outcomes in Schizophrenia

Patients with schizophrenia suffer from impairments of social cognition that represent mental operations underlying real-world functioning. Pharmacological approaches have been attempted to overcome social cognitive disturbances of schizophrenia, but only yielded insufficient effects. As an alternative approach, some types of neuromodulations, particularly non-invasive brain stimulation, e.g., transcranial direct current stimulation (tDCS), have been drawing attention. While previous studies have performed anodal tDCS at the frontal brain regions, we hypothesized anodal stimulation at the temporal region would improve social cognitive function on the basis of the neural circuit governing it. Thus, our data indicate multisession tDCS delivered to the left superior temporal sulcus improves social cognition in patients with schizophrenia. In the present chapter, we overview studies of tDCS on social cognition and discuss optimal brain regions to be targeted for ameliorating symptoms and cognitive disturbances of schizophrenia

Are attention-deficit/hyperactivity disorder symptoms associated with negative health outcomes in individuals with psychotic experiences? Findings from a cross-sectional study in Japan

ObjectiveAlthough research has indicated that the prevalence of attention-deficit/hyperactivity disorder (ADHD) may be elevated in individuals with psychotic disorders, as yet, there has been comparatively little research on this association and its effects among adults at the subclinical level. To address this deficit, the current study examined the association between psychotic experiences (PE) and ADHD symptoms in Japanese individuals and whether the presence of ADHD symptoms increases the risk for negative health outcomes in people with PE.MethodData were analyzed from an online sample of 1,452 individuals (age 18–89; 51.5% female) collected in 2021. Information on PE was obtained with the PRIME Screen-Revised (PS-R), while the Adult ADHD Self-Report Scale (ASRS) Screener was used to measure ADHD symptoms. Information was also obtained on a number of health outcomes including anxiety and depressive symptoms and suicidal ideation. Logistic regression was used to assess associations.ResultsIn a fully adjusted analysis PE were associated with almost three times higher odds for ADHD symptoms (OR: 2.92, 95%CI: 1.19–7.17). In an analysis that was restricted to individuals with PE, ADHD symptoms were associated with significantly increased odds for depressive symptoms, lifetime suicidal ideation, perceived stress and severe sleep problems.ConclusionADHD symptoms are present in some individuals with PE and increase the odds for several detrimental health outcomes in this population. Identifying co-occurring PE and ADHD/ADHD symptoms may facilitate treatment options and help prevent negative health outcomes in individuals with these conditions

生体内における定型、非定型抗精神病薬ドーパミン1型、2型およびセロトニン2型受容体結合に関する研究

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1093号,学位授与年月日：平成5年6月30日,学位授与年：199

Competence to Consent and Its Relationship With Cognitive Function in Patients With Schizophrenia

Decisional capacity to consent is an emerging ethical and legal concept, and is closely related to self-determination of patients facing important medical decisions or research participations. Recently, the MacArthur Competence Assessment Tool (MacCAT), a semi-structured interview consisting of four dimensions (Understanding, Appreciation, Reasoning, and Expression of a Choice), was developed to assess the decisional capacity. Decision-making capacity in a group of patients with schizophrenia, as measured by the MacCAT, has been shown to be impaired in comparison with healthy control people. However, this does not necessarily mean the presence of impaired decisional capacity in all cases. Considering the real-world practice of obtaining informed consent from patients with schizophrenia, it is important to evaluate the relationship between psychopathological features and decisional capacity of the illness. Negative symptoms of schizophrenia have been demonstrated to be related to the ability to understand information relevant to the decision, reason rationally, and appreciate a situation and its consequences. On the other hand, positive symptoms, such as delusions and hallucinations have been an inconsistent correlate of poor capacity. Furthermore, some studies indicate that impairment of cognitive function, a core symptom of schizophrenia, could be more largely associated with decisional capacity than positive and negative symptoms. Therefore, it is reasonable to assume cognitive enhancement would enlarge the capacity to consent and promote autonomy in medical treatment and research participation in patients with schizophrenia. Further studies are warranted to elucidate this and related issues

Neural correlates for intrinsic motivational deficits of schizophrenia; implication for therapeutics of cognitive impairment

The ultimate goal of the treatment of schizophrenia is recovery, a notion related to improvement of cognitive and social functioning. Cognitive remediation therapies (CRT), one of the most effective cognition enhancing methods, have been shown to moderately improve social functioning. For this purpose, intrinsic motivation, related to internal values such as interest and enjoyment, has been shown to play a key role. Although the impairment of intrinsic motivation is one of the characteristics of schizophrenia, its neural mechanisms remain unclear. This is related to the lack of feasible measures of intrinsic motivation, and its response to treatment. According to the self-determination theory (SDT), not only intrinsic motivation, but extrinsic motivation has been reported to enhance learning and memory in healthy subjects to some extent. This finding suggests the contribution of different types of motivation to potentiate the ability of the CRT to treat cognitive impairment of schizophrenia. In this paper, we provide a review of psychological characteristics, assessment methods, and neural correlates of intrinsic motivation in healthy subjects and patients with schizophrenia. Particularly, we focus on neuroimaging studies of intrinsic motivation, including our own. These considerations are relevant to enhancement of functional outcomes of schizophrenia