Current Psychopharmacology - Volume 2, Issue 1, 2013

In the last years, second generation antipsychotics have shown to be useful in the treatment of disorders with predominant impulse dyscontrol symptoms, in particular borderline personality disorder (BPD) and impulse control disorders (ICDs). The present review aims to provide a comprehensive examination of data from randomized controlled trials (RCTs), open label studies, and case reports concerning efficacy and safety of atypical antipsychotics in treating symptoms of impulsivity in BPD and ICDs. Empirical evidences in favor of these pharmacological agents are generally promising, but still initial and heterogeneous among different drugs. Data concerning clozapine are limited in BPD as well as in ICDs, as they usually derive from samples with concomitant psychotic symptoms or disorders. Concerning risperidone and its metabolite paliperidone, only few studies considered the effects on impulsive-aggressive behaviors in BPD patients. Some RCTs found that risperidone was effective against disruptive behaviors in adolescents, suggesting it could be tried in treating ICDs, such as intermittent explosive disorder. Quetiapine was found efficacious to control impulsivity in several open label studies of BPD and in one case report of trichotillomania (TTM). Ziprasidone has been poorly investigated in the treatment of impulsivebehavioral dyscontrol and the only RCT performed in BPD patients produced no significant effects on borderline psychopathology. At present, more solid and encouraging evidences of efficacy in treating impulsive disturbances of BPD have been provided from several RCTs of olanzapine and from fewer controlled studies of aripiprazole. Olanzapine was also found effective in a single RCT of TTM patient, while it has obtained controversial results in other ICDs. Aripiprazole also produced some benefit in the treatment of TTM, but findings are limited to case-reports. Further large-scale well-designed investigations are required to replicate and complete these data

A review of the literature on the use of second generation antipsychotics (SGA) in adolescent and adult patients with anorexia nervosa (AN) is presented. Open-label studies and case reports suggested beneficial effects of variable doses of olanzapine, quetiapine, risperidone and aripiprazole in AN subjects. Randomized, double-blind, controlled studies conducted mainly with olanzapine demonstrated its efficacy on specific psychopathological aspects of AN. Moreover, although not consistently, increases in Body Mass Index (BMI) or appetite with no significant side effects were also reported. Taken together, the data of olanzapine studies, even if with a number of different limitations, show that this pharmacological treatment can be effective in improving specific aspects of AN in adult but not in adolescent patients. Further studies are warranted to consolidate these findings. Quetiapine and aripiprazole seem to be potentially promising options in the treatment of severe adult and adolescent AN patients because of their lower propensity to induce weight gain, revealing positive psychopathological effects and good tolerability. Given the inherent cardiac risks associated with the treatment of low weight AN patients, care should be taken when SGA use is being considered. Moreover, although SGA use might be associated to several other side effects (increasing weight, developing glucose intolerance and/or diabetes, metabolic disturbances) little has been published on this topic in AN patients and only few of the analyzed studies have reported adverse reactions. The different mechanisms underlying these effects are therefore discussed. Future directions for pharmacologic treatment research in AN should include randomized controlled trials with different antipsychotic medications, inpatient versus outpatient trials and the assessment of medication effect for relapse prevention in weight-restored patients.

Pharmacological treatments of first episode schizophrenia are of particular relevance because most clinical and psychosocial deterioration with cognitive decline and changes in brain volume occurs in the first five years of disease onset. Although the efficacy of antipsychotic maintenance treatment has been demonstrated to reduce risk of relapse, nonadherence is common even in first episode schizophrenia patients. Antipsychotic long-acting injections (LAIs) could be an option in early treatment although international guidelines recommend their use in patients who have already experienced significant non-adherence and who have repeated relapse. At the present time there is some concern about the acceptability of LAIs in first episode schizophrenia: some studies suggest that LAI treatment is feasible in these patients because of distinct advantages in terms of better treatment adherence. In the present review, we analyze the few currently studies published on the use of risperidone long-acting injection (RLAI) to improve adherence in first episode schizophrenia. Further research is needed to support the routine use of LAIs and of the other second generation antipsychotic LAIs (olanzapine long-acting and paliperidone palmitato) in this population of patients to improve adherence.

Cognitive dysfunction underpins some of the psychopathology of schizophrenia, as well as contributes to the patient's impaired social and vocational functioning and has now been recognized as an intrinsic dimension linked to functional outcome. Despite a general consensus on the capacity of antipsychotics to improve the psychopathology of schizophrenia, the dispute concerning their impact on cognitive function is constantly open. We performed a selective review on the possible effects of antipsychotics, both of first and second generation, for a cognitive performance improvement. Other than the strict treatment, pharmacological effect and related aspects, such as dosage and pharmaco-induced brain structure modifications, placebo and practice effect issues have been considered. Interaction with specific cognitive interventions, such as remediation programs and enhancement treatments are discussed. On the basis of the current evidence-based findings, the hypothesis that cognition could be substantially influenced by antipsychotics has so far been demonstrated. Administering antipsychotic medications in an individually optimized manner seems to have the potential of improving cognitive aspects of schizophrenia, regardless of the kind of antipsychotic medication.

Over the last decade, the class of the atypical antipsychotics has become the gold standard for the treatment of bipolar disorder (BD), at least for its manic/mixed phases. This phenomenon has different explanations: first, the number of compounds with formal approvals for BD is higher in comparison with other mood-stabilizers including lithium and anticonvulsants. Second, the sample size of randomized controlled trials assessing the efficacy and safety of different pharmacological treatments is usually larger for most recently approved compounds (i.e., atypical agents for the treatment of BD). If the role of atypical antipsychotics is well-established in the treatment of BD, doubts still persist about their optimal efficacy as monotherapy vs combination treatment with other mood-stabilizers, in particular. In addition, a possible superiority in terms of efficacy for polytherapy needs to be balanced in relation to tolerability issues. The present article was aimed to review the state of the art in the field reviewing the latest evidence arising from international guidelines recommendations and meta-analyses.

Niemann-Pick disease type C (NPC) is a neurodegenerative lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function of either protein results in the endosomal accumulation of cholesterol and other lipids. The mechanism of neuro-toxicity induced by the lipid storage has not been well elucidated. Here, we report that NPC1-deficient Chinese hamster ovary cells exhibit increased release of arachidonic acid (AA) and synthesis of prostaglandin E2 compared with wild-type cells. The enhanced release of AA was inhibited by both treatment with the selective inhibitor of cytosolic phospholipase A2α (cPLA2α) and cultivation in lipoprotein-deficient medium. There was no difference in the expression of both cyclooxygenase-1 and -2 between NPC cells and wild-type cells. U18666A, a cholesterol transport-inhibiting agent commonly used to mimic NPC, also increased the release of AA in L929 mouse fibrosarcoma cells. Furthermore, U18666A induced formation of reactive oxygen species, and induced cell death and cell cycle delay/arrest in L929 cells. Interestingly, these responses induced by U18666A were much weaker in cPLA2α knockdown L929 cells. These results suggest that cPLA2α-AA pathway plays important roles in the cytotoxicity and the reactive oxygen species formation in NPC cells.

The first study on fatty acid composition of the postmortem brains of patients with psychiatric disorders was performed by Horrobin et al. in 1991, who found abnormalities in polyunsaturated fatty acids (PUFAs) in patients with schizophrenia. About a decade later, research in this field was re-started by Yao et al., followed by a number of other research groups. The results seem to show that the PUFA changes in psychiatric disorders may be specific to certain brain regions, but the underlying mechanisms remain unclear. Here we review these case-control studies of postmortem brain composition.

n-6 and n-3 polyunsaturated fatty acids (PUFAs) are essential dietary nutrients because they constitute part of the cell membrane, are a source of energy, and function as signaling molecules. Metabolites of PUFAs are strong lipid mediators and play a role in regulating inflammation. PUFAs are transported by specific proteins, and PUFAs and their metabolites act by binding to receptors. These transporter proteins and receptors are encoded by lipid-related genes. The neural system originates from neural stem/progenitor cells (NSPCs). NSPCs first proliferate, increasing their numbers, and then produce the neurons and glial cells that compose the complex neural circuits within the brain. Recently, our group and other groups have shown that PUFAs, their metabolites and lipid-related genes all affect the proliferation and differentiation of embryonic NSPCs, and these fatty acid signaling molecules are involved in neural development. Proper neural development is important for normal function of the adult brain, and impaired neuronal circuit formation causes long-lasting dysfunction. It is now widely accepted that impaired neural development increases an individual's susceptibility to the onset of psychiatric disorders (a concept known as the “neurodevelopmental theory”). Recent reports show evidence of an association between lipid-related genes and psychiatric disorders. In addition, PUFAs have been reported to have an ameliorative effect on various psychiatric disorders. A better understanding of neurodevelopmental regulation by PUFAs and their metabolites, as well as of the effects of PUFAs on psychiatric disorders, may provide important insight into the relationship between neural development and psychiatric disorders.

Autism spectrum disorders (ASD) are a cluster of developmental disorders, whose core symptoms can be attributed to abnormal development of the large-scale neural networks required for social communication. The impaired delivery of afferent signals has been proposed to be associated with impaired social interaction in ASD. Arachidonic acid (ARA) and docosahexaenoic acid (DHA) play key roles in the maturation of brain network. In particular, ARA promotes signal transduction related to neural function. It is therefore possible that supplementation with larger ARA doses added to DHA may mitigate the impaired social interaction observed in ASD. There have been no double-blind randomized placebo-controlled studies of the effect of large doses of ARA, added to DHA, on the impaired social interactions observed in ASD. This article presents the results of a 16-week double-blind randomized placebo-controlled trial in which high-dose ARA was added to DHA supplementation in individuals with ASD (n=13). The primary outcomes were measured using the Social Responsiveness Scale (SRS) and the secondary outcome measure was Autism Diagnostic Interview-revised (ADI-R) social and communication domains. Supplementation of larger doses of ARA added to DHA significantly improved SRS-measured communication and ADI-measured social communication. At the end of trial, the increase in plasma ARA levels from the baseline observed in the ARA treatment group was significantly higher compared to placebo group.