Lithium vs. valproate vs. olanzapine vs. quetiapine as maintenance monotherapy for bipolar disorder: a population‐based UK cohort study using electronic health records

It is unclear which maintenance treatment for bipolar disorder is superior in clinical practice. Randomized controlled head‐to‐head trials of available drugs either do not exist or are inconclusive. We aimed to compare rates of monotherapy treatment failure in individuals prescribed lithium, valproate, olanzapine or quetiapine by a population‐based cohort study using electronic health records. 5,089 patients with bipolar disorder were prescribed lithium (N=1,505), valproate (N=1,173) olanzapine (N=1,366) or quetiapine (N=1,075) as monotherapy. Treatment failure was defined as time to stopping medication or add‐on of another mood stabilizer, antipsychotic, antidepressant or benzodiazepine. In unadjusted analyses, the duration of successful monotherapy was longest in individuals treated with lithium. Treatment failure had occurred in 75% of those prescribed lithium by 2.05 years (95% CI: 1.63‐2.51), compared to 0.76 years (95% CI: 0.64‐0.84) for those prescribed quetiapine, 0.98 years (95% CI: 0.84‐1.18) for those prescribed valproate, and 1.13 years for those prescribed olanzapine (95% CI: 1.00‐1.31). Lithium's superiority remained in a propensity score matched analysis; when treatment failure was defined as stopping medication or add‐on of a mood stabilizer or antipsychotic; and when treatment failure was restricted to more than three months after commencing the study drug. Lithium appears to be more successful as monotherapy maintenance treatment than valproate, olanzapine or quetiapine. Lithium is often avoided because of its side effect profile, but alternative treatments may reduce the time to being prescribed more than one drug, with potential additive side effects of these treatments.     

Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action

Despite recent advances in understanding the pathophysiology of schizophrenia and the mechanisms of antipsychotic drug action, the development of biomarkers for diagnosis and therapeutic monitoring in schizophrenia remains challenging. Metabolomics provides a powerful approach to discover diagnostic and therapeutic biomarkers by analyzing global changes in an individual's metabolic profile in response to pathophysiological stimuli or drug intervention. In this study, we performed gas chromatography-mass spectrometry based metabolomic profiling in serum of unmedicated schizophrenic patients before and after an 8-week risperidone monotherapy, to detect potential biomarkers associated with schizophrenia and risperidone treatment. Twenty-two marker metabolites contributing to the complete separation of schizophrenic patients from matched healthy controls were identified, with citrate, palmitic acid, myo-inositol, and allantoin exhibiting the best combined classification performance. Twenty marker metabolites contributing to the complete separation between posttreatment and pretreatment patients were identified, with myo-inositol, uric acid, and tryptophan showing the maximum combined classification performance. Metabolic pathways including energy metabolism, antioxidant defense systems, neurotransmitter metabolism, fatty acid biosynthesis, and phospholipid metabolism were found to be disturbed in schizophrenic patients and partially normalized following risperidone therapy. Further study of these metabolites may facilitate the development of noninvasive biomarkers and more efficient therapeutic strategies for schizophrenia.     

Neurodevelopment and mood stabilizers

Mood disorders and schizophrenia share a number of common properties, including: genetic susceptibility; differences in brain structure and drug based therapy. Some genetic loci may even confer susceptibility for bipolar mood disorder and schizophrenia, and some atypical antipsychotic drugs are used as mood stabilizers. As schizophrenia is associated with aberrant neurodevelopment, could this also be true for mood disorders? Such changes could arise pre- or post-natal, however the recent interest in neurogenesis in the adult brain has suggested involvement of these later processes in the origins of mood disorders. Interestingly, the common mood stabilizing drugs, lithium, valproic acid (VPA) and carbamazepine, are teratogens, affecting a number of aspects of animal development. Recent work has shown that lithium and VPA interfere with normal cell development, and all three drugs affect neuronal morphology. The molecular basis for mood stabilizer action in the treatment of mood is unknown, however these studies have suggested both targets and potential mechanisms. Lithium directly inhibits two evolutionarily conserved signal transduction pathways: the protein kinase Glycogen Synthase Kinase-3 (GSK-3) and inositol signaling. VPA can up-regulate gene expression through inhibition of histone deacetylase (HDAC) and indirectly reduce GSK-3 activity. VPA effects are not conserved between cell types, and carbamazepine has no effect on the GSK-3 pathway. All three mood stabilizers suppress inositol signaling, results further supported by studies on the enzyme prolyl oligopeptidase (PO) and the sodium myo-inositol transporter (SMIT). Despite these intriguing observations, it remains unclear whether GSK-3, inositol signaling or both underlie the origins of bipolar disorder.     

Traitement pharmacologique du premier épisode psychotique

Pharmacological treatment has a central role in the treatment of a first episode psychosis. However, drug therapy must be viewed as within a framework of a global approach, whose aim is to facilitate the participation of the patient in the treatment regime. As the initial symptoms of psychotic disorders may often be atypical and complicated by co-morbidity, this can make both the early diagnosis and the choice of an appropriate treatment difficult. In a more dimensional approach to diagnosis rather than a categorical approach, it is important to identify the presence of affective symptoms (depressive or manic) which may necessitate the addition of either an antidepressant or a mood stabilizer. The indication for using atypical antipsychotic drugs as first choice in treatment has been firmly established in the current literature. These novel antipsychotic drugs are less prone to inducing undesirable side-effects, such as cognitive impairment and dysphoria, and appear to have a more favourable effect than conventional neuroleptics on the course of both depressive symptoms as well as hostile and aggressive behaviours. Furthermore, they seem to have a mood stabilizing effect, and are more easily accepted by the patients. Even though there is a reduced risk of acute extrapyramidal side-effects and late onset dyskinesia, the risk of weight gain as well as cardiovascular and endocrinological complications is considerable. This review article focuses on problems related to pharmacological treatment of first episode psychosis. It is the result of an extensive review of the current literature available on this field. The results have been discussed and organised in the form of clinical guidelines for the treatment of both non-affective and affective first episode psychoses.     

The binding of [3H]AF-DX 384 is reduced in the caudate-putamen of subjects with schizophrenia.

Clinical studies of cholinergic pharmacotherapy, together with the putative role of the muscarinic receptor system in the neurophysiology of human behavior, support a possible muscarinic cholinergic involvement in schizophrenia. The present study has measured the density of [3H]AF-DX 384 labelled receptors (muscarinic M2 and M4) in the caudate-putamen, obtained at autopsy, from 19 subjects who had schizophrenia, and 20 subjects who did not have schizophrenia. [3H]AF-DX 384 binding was reduced in caudate-putamen from schizophrenic subjects (104 +/- 10.3 vs 145 +/- 901 fmol mg(-1) TE; mean +/- s.e.; p = 0.007). Preliminary analysis of patient drug data as well as rat studies suggest that the reduced [3H]AF-DX 384 binding in caudate-putamen of schizophrenic subjects is not wholly due to antipsychotic drug treatment, or anticholinergic medication for the treatment of extrapyramidal effects. These data suggest that the muscarinic cholinergic system may be involved in the pathology of schizophrenia.     

Are Striatal Dopamine D4 Receptors Increased in Schizophrenia?

Abstract: The density of dopamine D₂-like receptors was determined using [³H]emonapride binding in putamen tissue taken postmortem from schizophrenic subjects and matched controls. A 72% increase in number of these receptors was identified in the schizophrenics, although three patients not receiving antipsychotic drug treatment before death exhibited receptor densities in the control range. Displacement of 1 n M [³H]emonapride binding by raclopride was used to define the contribution of the D₄ subtype of dopamine receptors to total [³H]emonapride binding. No evidence was obtained for the presence of D₄ receptors in putamen tissue from either control or schizophrenic subjects, indicating that the increase in D₂-like receptor density in schizophrenia is due not to an increase in number of D₄ sites in the disease, but to an up-regulation of D₂ or D₃ receptors probably induced by chronic treatment with antipsychotic drugs.     

Differential pharmacological regulation of drug efflux and pharmacoresistant schizophrenia

Pharmacoresistant schizophrenia is a significant impediment to the successful management of the disease. The expression and function of P-glycoprotein (P-gp) has recently been implicated in this phenomenon. P-gp is a multidrug efflux transporter that prevents drug substrates from crossing the blood-brain barrier (BBB). Although the direct interaction between individual antipsychotic agents and P-gp has been demonstrated, the effect of antipsychotic drug combinations used in disease management on P-gp transport function remains to be elucidated. This could have important clinical implications in some individuals as dosage adjustments based on plasma drug concentration changes may not always be appropriate if drug-drug interactions and the resulting changes in drug concentration in the brain are not considered. This paper introduces the potential impact that combination antipsychotic therapy may have on P-gp function at the BBB and discusses the consequences of this in the prevention and circumvention of unfavourable therapeutic response in schizophrenic disorders.     

Dopamine D3 receptors as a novel target for improving the treatment of schizophrenia

Schizophrenia is a complex and serious disorder which affects some 0.5-1.0% of the population. The disease generally begins in adolescence. This early onset, together with the progressive and often irreversible nature of schizophrenia, account for its high social cost. Positive symptoms, such as hallucinations, are generally well-controlled by antipsychotics, whereas cognitive and deficit symptoms are poorly-treated. All antipsychotic agents, irrespective of their overall receptor-binding profiles, interact with dopaminergic mechanisms that are known to be perturbed in schizophrenic patients. Dopamine exerts its actions via five classes of receptor, offering a broad palette of targets for the conception of novel antipsychotic agents. The present article focuses on the relevance of dopamine D3 receptors to the aetiology and treatment of schizophrenia. Experimental studies suggest that, as compared to other drugs, antipsychotic agents which preferentially block D3 receptors may possess therapeutic advantages, notably in the control of cognitive symptoms. The first clinical studies for the evaluation of this hypothesis have recently got underway.     

Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic,PAOPA: Examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia

Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia.     

Cognitive effects of olanzapine treatment in schizophrenia

Improvement in some but not all domains of cognition during treatment with the atypical antipsychotic drugs clozapine, quetiapine, olanzapine, and risperidone has been reported in some but not all studies. It has been recently suggested that these reports are an artifact, related to lessening of the impairment due to typical neuroleptic drugs and anticholinergic agents. The purpose of this study was to further test the hypothesis that olanzapine, an atypical antipsychotic drug reported to have anticholinergic properties, improves cognition in patients with schizophrenia, including domains of cognition related closely to work and social function (ie, verbal learning and memory) and that this improvement is independent of improvement in psychopathology. Thirty-four patients with schizophrenia who were partial responders to typical antipsychotic drug treatment were evaluated with a comprehensive neurocognitive battery, including measures of executive functioning; verbal and visual learning and memory; working memory; immediate, selective, and sustained attention; perceptual/motor processing; and motor skills prior to and following treatment with olanzapine for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology in patients treated with typical antipsychotic drugs. Subjects were switched to olanzapine (average dose 13.4 mg, range 5-20 mg) and reassessed following 6 weeks and 6 months of treatment. Significant improvement was noted in 9 of 19 cognitive tests, including measures of selective attention, verbal learning and memory, and verbal fluency. No cognitive test was worsened by olanzapine treatment. Improvements in the BPRS Total and Positive Symptom Subscale scores were noted. Improvements in verbal learning and memory, sustained attention, and psychomotor tracking were independent of improvement in psychopathology. These data suggest that olanzapine improved some but not all cognitive deficits in schizophrenia, including verbal memory, a cognitive domain impaired by anticholinergic drugs. The basis for the improvement in cognitive scores, which should lead to improvement in role functioning if real, is discussed.     

M4 agonists/5HT7 antagonists with potential as antischizophrenic drugs: serominic compounds

Chronic low-dose treatment of rats with the psychomimetic drug, phencyclidine, induces regionally specific metabolic and neurochemical changes in the CNS that mirror those observed in the brains of schizophrenic patients. Recent evidence suggests that drugs targeting serotoninergic and muscarinic receptors, and in particular 5-HT(7) antagonists and M(4) agonists, exert beneficial effects in this model of schizophrenia. Compounds that display this combined pattern of activity we refer to as serominic compounds. Based upon leads from natural product screening, we have designed and synthesised such serominic compounds, which are principally arylamidine derivatives of tetrahydroisoquinolines, and shown that they have the required serominic profile in ligand binding assays and show potential antipsychotic activity in functional assays.     

The influence of risperidone on cognitive functions in schizophrenia

Introduction of the antipsychotics of the second generation (SGA) into the therapy of schizophrenia roused expectations that, finally, the cognitive dysfunction in schizophrenia could be eliminated by psychopharmacological therapy. The purpose of the study was to verify the effect of atypical antipsychotic risperidone on cognitive functions in schizophrenic patients. The study was carried out upon 48 male schizophrenic patients aged 21-47 years who were switched from the antipsychotics of the first generation (FGA) to the antipsychotic risperidone, due to intolerance, during the treatment. Intelligence, abstract and concrete thinking and mental speed, attention, and short-term non-verbal memory prior to the switch, one month after the switch, and three months after the switch to risperidone, were evaluated. One month after the switch the number of subjects with severe impairment of intellectual abilities decreased significantly from 62% to 15% and after three months the number was even lower-8%. The impairment of concrete and abstract thinking and mental speed also showed the same tendencies of decrease. The improvement of the cognitive functioning after the switch from the antipsychotics of the first generation to the antipsychotic risperidone is explained by removal of the antipsychotics of the first generation from the therapy and the consequential disinhibition of secondary cognitive impairments and by decreased average dose of anticholinergic and decreased number of patients who need anticholinergic therapy beside risperidone. The possibility of clear pro-cognitive effect of risperidone is suggested and its verification is proposed with strict control of other factors that improve cognitive functioning of schizophrenic patients during the treatment.     

Selective disruption of dopamine D2-receptors/beta-arrestin2 signaling by mood stabilizers

Abstract

Mood stabilizers are a heterogeneous class of drugs having antidepressant and anti-manic effects in bipolar disorders, depression and schizophrenia. Despite wide clinical applications, the mechanisms underlying their shared actions and therapeutic specificity are unknown. Here, we examine the effects of the structurally unrelated mood stabilizers lamotrigine, lithium and valproate on G protein and beta-arrestin-dependent components of dopamine D2 receptor signaling and assess their contribution to the behavioral effects of these drugs. When administered chronically to mice lacking either D2 receptors or beta-arrestin 2, lamotrigine, lithium and valproate failed to affect Akt/GSK3 signaling as they do in normal littermates. This lack of effect on signaling resulted in a loss of responsiveness to mood stabilizers in tests assessing “antimanic” or “antidepressant”-like behavioral drug effects. This shows that mood stabilizers lamotrigine, lithium and valproate can exert behavioral effects in mice by disrupting the beta-arrestin 2-mediated regulation of Akt/GSK3 signaling by D2 dopamine receptors, thereby suggesting a shared mechanism for mood stabilizer selectivity.     

GABA Transporter-1 Deficiency Confers Schizophrenia-Like Behavioral Phenotypes

The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABA_A receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.     

Parasitosis, dopaminergic modulation and metabolic disturbances in schizophrenia: evolution of a hypothesis

Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia. Issues for further research have been suggested. Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance. Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. We believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia.     

Glutamate and Schizophrenia: Beyond the Dopamine Hypothesis

1. After 50 years of antipsychotic drug development focused on the dopamine D2 receptor, schizophrenia remains a chronic, disabling disorder for most affected individuals.2. Studies over the last decade demonstrate that administration of low doses of NMDA receptor antagonists can cause in normal subjects the negative symptoms, cognitive impairments and physiologic disturbances observed in schizophrenia.3. Furthermore, a number of recently identified risk genes for schizophrenia affect NMDA receptor function or glutamatergic neurotransmission.4. Placebo-controlled trials with agents that directly or indirectly activate the glycine modulatory site on the NMDA receptor have shown reduction in negative symptoms, improvement in cognition and in some cases reduction in positive symptoms in schizophrenic patients receiving concurrent antipsychotic medications.5. Thus, hypofunction of the NMDA receptor, possibly on critical GABAergic inter-neurons, may contribute to the pathophysiology of schizophrenia.     

Network-assisted investigation of antipsychotic drugs and their targets

Antipsychotic drugs are tranquilizing psychiatric medications primarily used in the treatment of schizophrenia and similar severe mental disorders. So far, most of these drugs have been discovered without knowing much on the molecular mechanisms of their actions. The available large amount of pharmacogenetics, pharmacometabolomics, and pharmacoproteomics data for many drugs makes it possible to systematically explore the molecular mechanisms underlying drug actions. In this study, we applied a unique network-based approach to investigate antipsychotic drugs and their targets. We first retrieved 43 antipsychotic drugs, 42 unique target genes, and 46 adverse drug interactions from the DrugBank database and then generated a drug-gene network and a drug-drug interaction network. Through drug-gene network analysis, we found that seven atypical antipsychotic drugs tended to form two clusters that could be defined by drugs with different target receptor profiles. In the drug-drug interaction network, we found that three drugs (zuclopenthixol, ziprasidone, and thiothixene) tended to have more adverse drug interactions than others, while clozapine had fewer adverse drug interactions. This investigation indicated that these antipsychotics might have different molecular mechanisms underlying the drug actions. This pilot network-assisted investigation of antipsychotics demonstrates that network-based analysis is useful for uncovering the molecular actions of antipsychotics.     

Off-label indications for atypical antipsychotics: A systematic review

INTRODUCTION: With the introduction of newer atypical antipsychotic agents, a question emerged, concerning their use as complementary pharmacotherapy or even as monotherapy in mental disorders other than psychosis. MATERIAL AND METHOD: MEDLINE was searched with the combination of each one of the key words: risperidone, olanzapine and quetiapine with key words that refered to every DSM-IV diagnosis other than schizophrenia and other psychotic disorders, bipolar disorder and dementia and memory disorders. All papers were scored on the basis of the JADAD index. RESULTS: The search returned 483 papers. The selection process restricted the sample to 59 papers concerning Risperidone, 37 concerning Olanzapine and 4 concerning Quetiapine (100 in total). Ten papers (7 concerning Risperidone and 3 concerning Olanzapine) had JADAD index above 2. Data suggest that further research would be of value concerning the use of risperidone in the treatment of refractory OCD, Pervasive Developmental disorder, stuttering and Tourette's syndrome, and the use of olanzapine for the treatment of refractory depression and borderline personality disorder. DISCUSSION: Data on the off-label usefulness of newer atypical antipsychotics are limited, but positive cues suggest that further research may provide with sufficient hard data to warrant the use of these agents in a broad spectrum of psychiatric disorders, either as monotherapy, or as an augmentation strategy.