Distribution and function of dopamine D1, D2 receptor]

Positron emission tomography (PET) techniques have made it possible to measure changes in target molecular in living human brain. PET can be used to investigate various brain functions such as receptors, transporters, enzymes and various biochemical pathways; therefore, it could be a powerful tool for molecular imaging of functional neurotransmission. Since dopamine is an important molecule for pathophysiology of Parkinson's disease and schizophrenia, we reviewed in vivo imaging studies focusing on dopaminergic transmission. Dopamine D2 receptor occupancy by antipsychotics and it's time-course have been measured using PET. This approach can provide in vivo pharmacological evidences of antipsychotics and establish the rational therapeutic strategy. PET is a powerful tool not only in the field of brain research but also drug discovery. On the other hand Dopamine D1 receptor is highly expressed in the prefrontal cortex, has been implicated in the control of working memory, seeking, craving, reward. We propose that dysfunction of Dopamine D1 receptor signalling in the prefrontal cortex may contribute to the negative symptoms and cognitive deficits seen in schizophrenia and we suggest that Dopamine D1 receptor binding and cerebral blood flow changes in ventral striatum play the important role of cigarette craving.     

New developments in the pharmacologic treatment of schizophrenia: editor's introduction.

In this issue we have tried to bring together a series of reviews describing new developments in the pharmacologic management of schizophrenia. Important progress is being made not only in medication development, but also in furthering our ability to use available treatments and treatment combinations in the most effective manner. Topics discussed include: the role of blood levels; alternative somatic treatments for nonresponding patients; the role of clozapine; putative mechanisms of action of novel antipsychotics; an overview of potential antipsychotic drugs under development; new findings in maintenance treatment; a review of the impact of neuroleptic treatment on the long-term course of schizophrenia; and a discussion of obstacles which must be overcome to ensure that the promise of treatment research can be fully realized.     

Investigation of molecular serum profiles associated with predisposition to antipsychotic-induced weight gain

Objectives. Metabolic disturbances are major adverse side effects in the treatment of schizophrenia patients with antipsychotics. A substantial proportion of patients discontinue treatment with second-generation antipsychotics due to weight gain. The objective of this study was to investigate molecular factors predisposing patients to the development of such metabolic disturbances. Methods. We investigated whether serum molecules measured before treatment initiation were associated with subsequent weight gain following a 6-week treatment with antipsychotics. The concentrations of 191 molecules were measured longitudinally in serum from 77 schizophrenia patients using multiplex immunoassays. Results. This showed that the levels of 10 serum molecules at T0 were significantly associated with ΔBMI, which included interleukin-6 receptor, epidermal growth factor and thyroid stimulating hormone. Conclusions. Our results suggest that patients who experience antipsychotic-induced weight gain have specific molecular alterations already prior to treatment. Further studies are required to validate and evaluate current findings in the context of response and side-effect development. This may ultimately lead to molecular tests that can aid in the selection of antipsychotic treatments.     

Theory in antipsychotic drug therapy for schizophrenia]

In Japan, antipsychotic polypharmacy with high doses for schizophrenia has been traditionally used. However, antipsychotic polyphamacy with high doses provide disadvantages for patient. Recent PET studies show that dopamine D2 occupancy with antipsychotics is important for the treatment of schizophrenia. First, antipsychotics become effective only at which their D2 occupancy exceeds 65%. Second, antipsychotics with D2 occupancy below 90% rarely causes occupancy exceeds 65%. Second, antipsychotics with D2 occupancy below 90% rarely causes extrapyramidal side effect. These results suggest that monopharmacy which uses a single antipsychotic agent with appropriate dose is recommended for schizophrenia treatment.     

The treatment of tardive dyskinesia and tardive dystonia

The enthusiasm produced by the introduction of antipsychotic medication in the 1950s gave way to a certain frustration in the 1970s and 1980s. Despite the development of a large number of new drugs, little progress was made in treatment because these new agents were, in essence, therapeutically equivalent. This lack of progress was perhaps also related to an emphasis on tardive dyskinesia in the 1970s, i.e., the preoccupation with a negative effect of treatment. The reverse is taking place today. Clozapine and the other atypical antipsychotics are associated in people's minds with fewer or absent extrapyramidal symptoms and less tardive dyskinesia than the older typical agents. As a result, a certain amount of complacency exists. Tardive dyskinesia not only may be painful and disfiguring, but it also predicts poor outcome in patients with schizophrenia. Although many treatments have been tried, none have proven completely efficacious. The best treatment for tardive dyskinesia and dystonia is prevention, which is a function of medication choice. Pharmacologic interventions for tardive dyskinesia include clozapine and the other atypical antipsychotics. If typical antipsychotics must be used, they should be started at the lowest possible levels. Studies of risperidone suggest that it, too, should be used at very low doses to minimize the risk of tardive dyskinesia. It is also possible that schizophrenic patients taking atypical antipsychotics may experience fewer spontaneous dyskinesias, although further study is warranted.     

Psychiatric opinion and antipsychotic selection in the management of schizophrenia

OBJECTIVES: This study examined psychiatrists' opinions regarding the use of second-generation antipsychotics for treatment-resistant schizophrenia. It then sought to identify factors associated with these opinions. METHODS: A national survey was conducted (September 2003-January 2004) of psychiatrists engaged in the management of patients with schizophrenia. RESULTS: Among survey respondents (N=431), most psychiatrists (88%) believed that one or more of the five currently available second-generation antipsychotics could improve treatment-resistant positive symptoms after a failed trial of optimal oral haloperidol treatment. Psychiatrists who reported familiarity with schizophrenia practice guidelines were more likely to have high levels of optimism that these medications improve positive symptoms (odds ratio [OR]=3.6, 95% confidence interval [CI]=1.4-9.3, p=.009). Psychiatrists who met with a pharmaceutical representative at least once a week were also more likely to have high levels of optimism toward second-generation antipsychotics (OR=2.3, CI=1.4-3.9, p=.001). CONCLUSIONS: Reported familiarity with treatment guidelines and frequent contact with pharmaceutical representatives appear to be associated with optimism toward second-generation antipsychotics.     

Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness

BACKGROUND: Truly effective treatments for schizophrenia require much more than clinical efficacy. Symptom improvement is all that is required to demonstrate clinical efficacy. However, for a treatment to be effective in a wide-ranging manner, improvement in various life domains, such as social functioning, independent living, and employment, should also be found. Thus, a much wider range of improvements, not widely produced by previous treatments, is required to take treatment for schizophrenia to a new level of effectiveness. CONSENSUS PROCESS: A teleconference consensus meeting was held with the bylined authors on December 10, 2002, to explore the factors that hinder the most effective treatments for schizophrenia. We argue that a possible unifying factor underlying these apparently disparate domains of effective treatment is cognitive functioning, which is impaired in people with schizophrenia. Treatment of cognitive dysfunction may have a central role in increasing the breadth of effective treatment for schizophrenia. CONCLUSIONS: Novel antipsychotics and specific cognitive-enhancing medications have preliminarily been shown to have cognitive benefits that might lead to broader effectiveness of treatments, eventually reflected in improvements in the daily lives of patients. These treatments may have their greatest impact when combined with focused psychological interventions. While the research to date does not provide a large number of successes, this area will be one of considerable research interest for the next decade, with developments likely to be very important to clinicians treating patients with schizophrenia.     

Positron emission tomography and single photon emission CT molecular imaging in schizophrenia

We reviewed findings from PET and SPECT studies that have contributed to our understanding of the pathophysiology and treatment of schizophrenia. The most robust set of findings pertains to imaging of presynaptic dopaminergic function in the striatum. The results of these studies have been consistent in showing that schizophrenia, at least during episodes of illness exacerbation, is associated with increased activity of DA neurons; this increased presynaptic activity is associated with positive symptoms and good therapeutic response. Studies of cortical DA function are less numerous and less consistent. In the future, technical advances in PET instrumentation and radioligand development should contribute to a clarification of the role of prefrontal DA in the cognitive impairment that is presented by these patients. An important drawback of the literature in this field is the generally low number of subjects that are included in studies (typically less than 20 per group). Small samples are necessitated by the cost of these investigations, but also, in some instances, to the difficulty in recruiting appropriate clinical subjects (such as drug-free patients who have schizophrenia). In conditions that are characterized by marked heterogeneity, such as major depressive disorders, this factor is bound to yield divergent results across studies. Another source of discrepancy is the variety of technical approaches to data acquisition and analysis. For example, analytical methods range from "empirical" or "semiquantitative" (typically a region of interest to a region of reference ratio measured at one time point) to model-based methods that use an arterial input function. The limitations that are associated with empirical analytical methods might account for artifactual results, especially when the effect size of the between-group difference and the number of subjects are small [149]. In addressing these limitations it will be important to increase the availability of these techniques beyond a few academic centers, to promote multi-center studies in well-characterized populations, and to standardize analytical methods. Until recently, SPECT was the only widely available technique, and SPECT studies have provided a substantial contribution to this field. With the current increase in PET camera availability, the development of [18F]-based molecular imaging probes will provide unique opportunities for further dissemination of these techniques. The article reviewed seminal findings obtained with PET and SPECT molecular imaging of schizophrenia. These techniques do not play a major role in the diagnosis and treatment of this disorder, remain essentially research tools. The results that have been produced by this field to date suggest that PET will significantly contribute to unraveling the biologic bases of psychiatric disorders and may contribute to their clinical management. Moreover, it is foreseeable that PET will become increasingly involved in the development of new psychiatric medications. Expanding the availability of PET and the current radiopharmaceutical portfolio will be critical for these predictions to become reality.     

Integrating pharmacological and psychosocial treatments for schizophrenia

OBJECTIVE: The objective of this study was to develop principles of combining pharmacological and psychosocial treatment that can be useful for clinicians who are treating patients with schizophrenia. METHOD: Research studies in schizophrenia that controlled both pharmacological and psychosocial treatments were reviewed. These included studies using conventional and newer antipsychotics as well as a number of psychosocial methods. RESULTS: The interactions between the forms of treatment appear to be more than merely additive, since each can enhance the effects of the other. Drug and psychosocial treatments may affect different outcome domains, with the former affecting symptoms and the later affecting social outcomes. Recent studies using newer antipsychotics suggest that these agents improve the participation of patients in psychosocial treatments. CONCLUSION: Understanding the interactions between psychosocial and pharmacological treatments can be useful for clinicians who are developing treatment strategies for patients with schizophrenia. Newer agents with different side-effect profiles and broader effectiveness appear to have improved the outcomes of psychosocial treatments.     

Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or Cul-de-sac?

Negative symptoms of schizophrenia are debilitating and they contribute to poor outcome in schizophrenia. Initial enthusiasm that second-generation antipsychotics would prove to be powerful agents to improve negative symptoms has given way to relative pessimism that the effects of current pharmacological treatments are at best modest. METHOD: A review of the current 'state-of-play' of pharmacological treatments for negative symptoms in schizophrenia. RESULTS: Treatment results to date have been largely disappointing. The evidence for efficacy of second-generation antipsychotics is reviewed. CONCLUSION: The measurement and treatment trials methodology for the evaluation of negative symptoms need additional refinement before therapeutic optimism that better treatments for negative symptoms can be realized.     

PET and SPECT imaging in psychiatric disorders.

OBJECTIVES: To review recent findings from positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigate the pathophysiology and treatment of schizophrenia, depression, and dementia. METHODS: We carried out a review of the literature. RESULTS: PET and SPECT studies have provided evidence of dopamine system dysregulation in patients with schizophrenia and variable loss of monoamines in patients with depression. Antipsychotic response has been demonstrated to be associated with blockade of dopamine D2 receptors, and antidepressant response has now been linked to blockade of serotonin transporter receptors. PET and SPECT have been extensively evaluated as diagnostic procedures for dementia. Substantial progress has been made in developing radioligands that bind to amyloid deposits in the brain, which should provide new opportunities for early diagnosis and treatment monitoring in Alzheimer's disease. CONCLUSION: Advances in PET and SPECT imaging have provided new insights into the biology of major psychiatric disorders and their treatment. In the future, we can expect that these imaging techniques will become more central to the management of psychiatric disorders.     

Treating Older Adults With Schizophrenia: Challenges and Opportunities

Schizophrenia affects people of all age groups. Treatment plans for older adults with schizophrenia must consider the effects of age on the course of the illness as well as on the response to antipsychotics and to psychosocial interventions. Positive symptoms of schizophrenia tend to become less severe, substance abuse becomes less common, and mental health functioning often improves. Hospitalizations are more likely to be due to physical problems rather than psychotic relapses. Physical comorbidity is a rule, however, and older age is a risk factor for most side effects of antipsychotics, including metabolic syndrome and movement disorders. We recently reported high rates of adverse events and medication discontinuation along with limited effectiveness of commonly used atypical antipsychotics in older adults. Psychosocial interventions such as cognitive behavioral social skills training are efficacious in improving functioning in older adults with schizophrenia. In formulating treatment plans for this population, a balanced approach combining cautious antipsychotic medication use with psychosocial interventions is recommended. Antipsychotic medications should generally be used in lower doses in older adults. Close monitoring for side effects and effectiveness of the medications and a watchful eye on their risk:benefit ratio are critical. In a minority of patients it may be possible to discontinue medications. Sustained remission of schizophrenia after decades of illness is not rare, especially in persons who receive appropriate treatment and psychosocial support—there can be light at the end of a long tunnel.Key words: schizophrenia, aging, antipsychotics, psychosocial treatments, cognition, psychosis     

Oxidative damage and schizophrenia: the potential benefit by atypical antipsychotics

There is evidence to suggest the derangement of the oxidant and antioxidant defense system in schizophrenia. The present study examined the effect of atypical antipsychotics on lipid peroxidation, superoxide dismutase (SOD) and ascorbic acid. For this purpose, a prospective, open-label, 8-week study design was utilized. Serum SOD, serum malondialdehyde (MDA) and plasma ascorbic acid were estimated. Schizophrenic patients (n = 48) were compared with age- and sex-matched healthy volunteers (n = 40). There was a significant increase in serum SOD, serum MDA and a decrease in plasma ascorbic acid in schizophrenic patients as compared to control subjects. The trend altered significantly after the treatment with atypical antipsychotics. The results of the Brief Psychiatric Rating Scale for schizophrenia also improved with the treatment. The findings indicate an involvement of free radicals in schizophrenia and its modification by treatment with atypical antipsychotics. This study can also be used as a predictor of drug response by atypical antipsychotics in schizophrenia.     

The effects of antipsychotic treatment on cerebral structure and function in schizophrenia

This paper analyses the effects of antipsychotic drug treatment on cerebral structure and function in schizophrenia reviewing qualitatively some of the relevant literature on the issue. Magnetic resonance imaging (MRI) studies of brain morphology in patients at different stages of illness and after varying times of neuroleptic exposure and longitudinal studies show possible different effects of first and second generation antipsychotics. This is true also for functional parameters, such as regional cerebral blood flow and metabolism, analysed, both in resting condition and after specific activation paradigms, with such diverse techniques as positron emission tomography (PET), single photon emission computed tomography (SPECT), functional MRI and MR spectroscopy. The possible molecular mechanisms underlying such differences and whether they represent direct drug effects or indirect consequences of their different and specific interactions with the ‘natural’ pathophysiological trajectory of brain abnormalities in schizophrenia are matter of present research and debate.     

Racial disparities in the use of second-generation antipsychotics for the treatment of schizophrenia

OBJECTIVE: Despite recommendations that second-generation antipsychotics be used as first-line treatment for schizophrenia, previous studies have shown that blacks are less likely than whites to receive these newer drugs. This study determined the rate at which second-generation antipsychotics were prescribed to whites and blacks with schizophrenia who were treated as outpatients. METHODS: Data were collected from a community mental health clinic affiliated with an academic center in Rochester, New York. Multivariate logistic regression was used to examine the association between race and the receipt of a second-generation antipsychotic. RESULTS: Data were available for 456 patients: 276 whites and 180 blacks. Ninety-five percent received a second-generation antipsychotic. Whites were approximately six times more likely than blacks to receive a second-generation medication, after the analysis controlled for clinical and sociodemographic factors (p<.001). Most of this difference appeared to be driven by a disparity in the use of clozapine. CONCLUSIONS: In this sample, blacks were less likely than whites to receive second-generation antipsychotics, demonstrating a persistent gap in the quality of care for patients with schizophrenia.     

Positron emission tomography imaging for the assessment of mild traumatic brain injury and chronic traumatic encephalopathy: recent advances in radiotracers

A chronic phase following repetitive mild traumatic brain injury can present as chronic traumatic encephalopathy in some cases,which requires a neuropathological examination to make a definitive diagnosis.Positron emission tomography(PET)is a molecular imaging modality that has high sensitivity for detecting even very small molecular changes,and can be used to quantitatively measure a range of molecular biological processes in the brain using different radioactive tracers.Functional changes have also been reported in patients with different forms of traumatic brain injury,especially mild traumatic brain injury and subsequent chronic traumatic encephalopathy.Thus,PET provides a novel approach for the further evaluation of mild traumatic brain injury at molecular levels.In this review,we discuss the recent advances in PET imaging with different radiotracers,including radioligands for PET imaging of glucose metabolism,tau,amyloid-beta,γ-aminobutyric acid type A receptors,and neuroinflammation,in the identification of altered neurological function.These novel radiolabeled ligands are likely to have widespread clinical application,and may be helpful for the treatment of mild traumatic brain injury.Moreover,PET functional imaging with different ligands can be used in the future to perform largescale and sequential studies exploring the time-dependent changes that occur in mild traumatic brain injury.     

The effects of antipsychotic treatment on cerebral structure and function in schizophrenia

This paper analyses the effects of antipsychotic drug treatment on cerebral structure and function in schizophrenia reviewing qualitatively some of the relevant literature on the issue. Magnetic resonance imaging (MRI) studies of brain morphology in patients at different stages of illness and after varying times of neuroleptic exposure and longitudinal studies show possible different effects of first and second generation antipsychotics. This is true also for functional parameters, such as regional cerebral blood flow and metabolism, analysed, both in resting condition and after specific activation paradigms, with such diverse techniques as positron emission tomography (PET), single photon emission computed tomography (SPECT), functional MRI and MR spectroscopy. The possible molecular mechanisms underlying such differences and whether they represent direct drug effects or indirect consequences of their different and specific interactions with the 'natural' pathophysiological trajectory of brain abnormalities in schizophrenia are matter of present research and debate.     

Past and present progress in the pharmacologic treatment of schizophrenia

Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.     

Atypical antipsychotics in elderly patients with dementia or schizophrenia: review of recent literature

Atypical antipsychotics have become a common pharmacologic option for the treatment of various psychiatric and behavioral symptoms in older adults, although these medications have been officially approved by the U.S. Food and Drug Administration for use only in schizophrenia and bipolar disorder. Despite the widespread use of these agents, there is a relative shortage of rigorously conducted trials. This review focuses on recently published randomized, blinded, controlled trials involving the use of atypical antipsychotics in elderly patients with dementia (n = 9) or schizophrenia (n = 3), with some discussion of published large, open-label studies and a few unpublished controlled trials. In general, the studies of patients with dementia reported modest efficacy of atypical antipsychotics when compared to placebo and conventional antipsychotics. In addition, an advantage in terms of motor side effects was consistently noted with atypical antipsychotics when compared to conventional antipsychotics. The studies have also shown, however, a greater risk of mortality and adverse cerebrovascular events with several of these agents than with placebo in individuals with dementia. There are insufficient data comparing atypical antipsychotics to one another. In the trials involving elderly persons with schizophrenia, atypical antipsychotics were associated with significant improvements in psychopathology; differences in efficacy among atypical antipsychotics were unclear. A careful consideration of the risk-benefit ratio of atypical antipsychotics, as well as that of available alternative treatments, is needed for each individual elderly patient. Clinical judgment, caution, and consent should be the watchwords in this area of psychopharmacology.     

New developments in the pharmacotherapy of schizophrenia

This review summarizes current key research strategies and the most prominently pursued new potential treatments for schizophrenia. First, new routes of administration for second generation antipsychotics are presented. These include rapidly dissolving tablets, drops and sirups as well as new intramuscular formulations. Newly available short acting and long acting (depot) antipsychotics complement oral antipsychotics so that the full spectrum of routes of administration is now available for second generation antipsychotics. Next to antipsychotic polypharmacy, in which two or more antipsychotics are combined, pharmacological add-on treatments, mainly with benzodiazepines, antidepressants and mood stabilizers enjoy increasing popularity. Most of this practice is driven by personal preferences, clinical experience and marketing rather than evidence based medicine. New pharmacological mechanisms currently utilized in advanced states of development include partial dopamine D2-receptor agonism, supplementation with glutamatergic agents, estrogen and omega-3-fatty acids. While the concept of partial D1-agonism has already led to the successful launch of a new antipsychotic, aripiprazole, the other attempts to improve therapeutic response in schizophrenia patients have so far provided equivocal results. It is argued that they may be helpful for certain subgroups or specific symptoms of schizophrenia patients. In conclusion, many exciting new pharmacological leads are currently pursued and this will very likely augment the options for treating patients with schizophrenia.