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The use of atypical antipsychotic drugs in the elderly has become wider and wider in recent years; in fact, these agents have novel receptor binding profiles, good efficacy with regard to negative symptoms, and reduced extrapyramidal symptoms. However, in recent years, the use of both conventional and atypical antipsychotics has been widely debated for concerns about their safety in elderly patients affected with dementia and the possible risks for stroke and sudden death. A MEDLINE search was made using the words elderly, atypical antipsychotics, use, schizophrenia, psychosis, mood disorders, dementia, behavioral disorders, and adverse events. Some personal studies were also considered. This paper reports the receptor binding profiles and the main mechanism of action of these drugs, together with their main use in psychiatry and the possible adverse events in elderly people.

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.

Background:Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).Methods:Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.Results:All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily).Conclusions:All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.

SummaryOur systematic review and meta-analysis of observational studies indicated that the use of antipsychotics was associated with a nearly 1.5-fold increase in the risk of fracture. First-generation antipsychotics (FGAs) appeared to carry a higher risk of fracture than second-generation antipsychotics (SGAs).IntroductionThe risk of fractures associated with the use of antipsychotic medications has inconsistent evidence between different drug classes. A systematic review and meta-analysis was conducted to evaluate whether there is an association between the use of antipsychotic drugs and fractures.MethodsSearches were conducted through the PubMed and EMBASE databases to identify observational studies that had reported a quantitative estimate of the association between use of antipsychotics and fractures. The summary risk was derived from random effects meta-analysis.ResultsThe search yielded 19 observational studies (n = 544,811 participants) with 80,835 fracture cases. Compared with nonuse, use of FGAs was associated with a significantly higher risk for hip fractures (OR 1.67, 95% CI, 1.45–1.93), and use of second generation antipsychotics (SGAs) was associated with an attenuated but still significant risk for hip fractures (OR 1.33, 95% CI, 1.11–1.58). The risk of fractures associated with individual classes of antipsychotic users was heterogeneous, and odds ratios ranged from 1.24 to 2.01. Chlorpromazine was associated with the highest risk (OR 2.01, 95% CI 1.43–2.83), while Risperidone was associated with the lowest risk of fracture (OR 1.24, 95% CI 0.95–1.83).ConclusionsFGA users were at a higher risk of hip fracture than SGA users. Both FGAs and SGAs were associated with an increased risk of fractures, especially among the older population. Therefore, the benefit of the off-label use of antipsychotics in elderly patients should be weighed against any risks for fracture.

Strong association between homocysteine (Hcy) and metabolic syndrome (MetS) is documented in individuals with schizophrenia and it is suggested that alterations in Hcy levels might be secondary to metabolic changes induced by atypical antipsychotics (AA). Serum paraoxonase (PON-1) activity, which is negatively affected by increased Hcy concentrations are lower in schizophrenia, and this may impact the development of metabolic side effects. Forty-five subjects with schizophrenia and 43 healthy volunteers, matched according to age, gender, smoking habits, and MetS predictors, were enrolled in this study to examine how Hcy level, PON-1 activity, and MetS indicators influence each other in schizophrenic individuals on AA treatment. Serum Hcy concentrations were significantly higher (15 ± 8 μmol/L vs 12 ± 3 μmol/L), and PON activity tended to be impaired (182±82 U/L vs 216 ± 110 U/L) in schizophrenia. Serum Hcy concentrations were not different between subjects with and without metabolic syndrome in study (14±4 μmol/L and 16±9 μmol/L) and control groups (12±3 μmol/L and 13±7 μmol/L), respectively. Similarly, PON and aryl esterase (AE) activities were not different between subjects with and without metabolic syndrome in study (PON: 185±100 U/L and 181±76 U/L; AE: 84±34 kU/L and 89±20 kU/L) and control (PON: 215±111 U/L and 216±113 U/L; AE: 83±27 kU/L and 88±33 kU/L) groups, respectively. . Hcy levels and MetS predictors were not statistically correlated. Results indicate that schizophrenic subjects on AA treatment have increased levels of Hcy compared to healthy controls and this is not influenced by the presence of MetS. Şizofreni olgularında homosistein (Hcy) ve metabolik sendrom (MetS) arasında güçlü ilişki olduğu bildirilmiş ve Hcy düzeylerindeki artışın atipik antipsikotikler (AA) ile uyarılan metabolik değişikliklere bağlı gelişebileceği düşünülmüştür. Artmış Hcy düzeylerinin negatif yönde etkilediği serum paraoksanaz (PON-1) aktivitesi, şizofrenili bireylerde düşük bulunmaktadır ve bu durumun metabolik yan etkilere neden olabileceği öne sürülmektedir. Bu çalışmada, AA tedavisi alan şizofreni kişilerde Hcy düzeyleri, PON-1 activitesi ve MetS indikatörlerinin birbirlerinden nasıl etkilendiğini incelemek üzere yaş, cinsiyet, sigara alışkanlığı ve MetS göstergelerine göre eşleştirilmiş 45 şizofreni olgusu ve 43 sağlıklı kontrol ile çalışıldı. Şizofreni olgularında serum Hcy düzeyleri anlamlı olarak yüksek (15 ± 8 μmol/L ve 12 ± 3 μmol/L) bulunurken, PON aktivitesinde (182±82 U/L ve 216 ± 110 U/L) azalma eğilimi olduğu gözlendi. Metabolik sendromu olan ve olmayan bireylerin Hcy konsantrasyonları arasında fark yoktu (Şizofreni grubunda sırasıyla, 14±4 μmol/L ve 16±9 μmol/L; Kontrol grubunda sırasıyla, 12±3 μmol/L and 13±7 μmol/L). Benzer şekilde, PON ve aril esteraz (AE) aktiviteleri değerlendirildiğinde metabolik sendromu olan ve olmayan şizofreni grubundaki bireylerin (PON: sırasıyla, 185±100 U/L ve 181±76 U/L; AE: sırasıyla, 84±34 kU/L ve 89±20 kU/L) ve kontrol grubundaki bireylerin (PON: sırasıyla, 215±111 U/L ve 216±113 U/L; AE: sırasıyla, 83±27 kU/L ve 88±33 kU/L) enzim aktivitelerinde fark bulunmadı.Hcy düzeyleri ile MetS göstergeleri arasında istatistiksel ilişki saptanmadı. Sonuçlara göre, AA tedavisi alan şizofreni olgularında Hcy düzeyleri sağlıklı kontrollere göre daha yüksektir ve bu durum MetS varlığından etkilenmemektedir.

Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, α -adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

Background: Pharmacological approaches are widely used for post-traumatic stress disorder (PTSD) despite uncertainty over efficacy. Objectives: To determine the efficacy of all pharmacological approaches, including monotherapy, augmentation and head-to-head approaches (drug versus drug, drug versus psychotherapy), in reducing PTSD symptom severity. Method: A systematic review and meta-analysis of randomised controlled trials were undertaken; 115 studies were included. Results: Selective serotonin reuptake inhibitors (SSRIs) were found to be statistically superior to placebo in reduction of PTSD symptoms but the effect size was small (standardised mean difference −0.28, 95% CI −0.39 to −0.17). For individual monotherapy agents compared to placebo in two or more studies, we found small statistically significant evidence for the antidepressants fluoxetine, paroxetine, sertraline, venlafaxine and the antipsychotic quetiapine. For pharmacological augmentation, we found small statistically significant evidence for prazosin and risperidone. Conclusions: Some medications have a small positive effect on reducing PTSD symptom severity and can be considered as potential monotherapy treatments; these include fluoxetine, paroxetine, sertraline, venlafaxine and quetiapine. Two medications, prazosin and risperidone, also have a small positive effect when used to augment pharmacological monotherapy. There was no evidence of superiority for one intervention over another in the small number of head-to-head comparison studies. * Our review found evidence of a small positive effect for a handful of medications, which can reduce the symptom severity in post-traumatic stress disorder. * These were fluoxetine, paroxetine, sertraline, venlafaxine and the antipsychotic quetiapine when used as monotherapy, prazosin and risperidone for augmentation.

Atypical antipsychotics (AAP) are the prevailing form of schizophrenia treatment today due to their low side effects and superior efficacy. Nevertheless, some issues still need to be addressed. First, there are still a large number of patients with treatment-resistant schizophrenia (TRS), which has led to a growing trend to resort to AAP polypharmacy with few side effects. Most clinical treatment guidelines recommend clozapine monotherapy in TRS, but around one third of schizophrenic patients fail to respond to clozapine. For these patients, with clozapine-resistant schizophrenia AAP polypharmacy is a common strategy with a continually growing evidence base. Second, AAP generally have great risks for developing metabolic syndrome, such as weight gain, abnormality in glucose, and lipid metabolism. These metabolic side effects have become huge stumbling blocks in today’s schizophrenia treatment that aims to improve patients’ quality of life as well as symptoms. The exact reasons why this particular syndrome occurs in patients treated with AAP is as yet unclear though factors such as interaction of AAP with neurotransmitter receptors, genetic pholymorphisms, type of AAPs, length of AAP use, and life style of schizophrenic patients that may contribute to its development. The present article aimed to review the evidence underlying these key issues and provide the most reasonable interpretations to expand the overall scope of antipsychotics usage.

Dementia affects about 47 million people worldwide, number expected to exponentially increase within 30 years. Alzheimer’s disease (AD) is the most common dementia type, accounting on its own for almost 70% of all dementia cases. Behavioral and psychological symptoms (BPSD) frequently occur during the disease progression; to treat agitation, aggressiveness, delusions and hallucinations, the use of antipsychotic drugs should be limited, due to their safety issues. In this literature review regarding the use of antipsychotics for treating BPSD in dementia, the advantages and limitation of antipsychotic drugs have been evaluated. The available medications for the management of behavioral and psychological symptoms are the antipsychotics, classed into typical and atypical, depending on their action on dopamine and serotonin receptors. First generation, or typical, antipsychotics exhibit lack of tolerability and display a broad range of side effects such as sedation, anticholinergic effects and extrapyramidal symptoms. Atypical, or second generation, antipsychotics bind more selectively to dopamine receptors and simultaneously block serotonin receptors, resulting in higher tolerability. High attention should be paid to the management of therapy interruption or switch between antipsychotics, to limit the possible rebound effect. Several switching strategies may be adopted, and clinicians should “tailor” therapies, accounting for patients’ symptoms, comorbidities, polytherapies and frailty.