Developments in antipsychotic therapy with regard to hypotheses for schizophrenia

The typical antipsychotic drugs like chlorpromazine and haloperidol were discovered by serendipity in the 1950s. A number of so-called "me too" drugs with similar chemical structures and modes of action were marketed in the subsequent years. The first atypical antipsychotic, clozapine, was an exception because it lacked some of the pharmacological properties of the typical antipsychotics related to the extrapyrimidal motor system. This unique feature of clozapine significantly broadened understanding of the mode of action of antipsychotics, and created new hypotheses for schizophrenia. Hypothesis-orientated development of new drugs was only recently initiated. Abnormalities of the immune system in schizophrenia are being increasingly discussed: shifts in the levels of T helper cells subsets 1 and 2 (Th1 and Th2) have been observed, and studies with risperidone and the cyclooxengenase (COX2) inhibitor celecoxib as an add-on therapy have provided very promising results. The glutamate N-methyl-D-aspartate (NMDA) receptors have also been investigated in relation to neuropathological abnormalities in prefrontal areas of the brain of patients with schizophrenia. This may lead to new technologies like artificial networks related to the glutamate NMDA receptor system. New molecular biological techniques used in pharmacogenomics and proteomics offer new and exciting directions for future drug developments.     

Pharmacogenetics and outcome with antipsychotic drugs

Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h²~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.     

The biology of schizophrenia

Schizophrenia is an illness where the clinical signs and symptoms, course, and cognitive characteristics are well described. Successful pharmacological treatments do exist, even though they are likely palliative. However, this broad knowledge base has not yet led to the identification of its pathophysiology or etiology The risk factors for schizophrenia are most prominently genetic and scientists anticipate that contributions from the new genetic information in the human genome will help progress towards discovering a disease mechanism. Brain-imaging techniques have opened up the schizophrenic brain for direct inquiries, in terms of structure, neurochemisiry, and function. New proposals for diagnosis include grouping schizophrenia together with schizophrenia-related personality disorders into the same disease entity, and calling this schizophrenia spectrum disorder. New hypotheses of pathophysiology do not overlook dopamine as playing a major role, but do emphasize the participation of integrative neural systems in the expression of the illness and of the limbic system in generating symptoms. Critical observations for future discovery are likely to arise from molecular genetics, combined with hypothesis-generating experiments using brain imaging and human postmortem tissue.     

Treatment mechanisms: traditional and new antipsychotic drugs

The first generation of antipsychotic drugs was discovered in the 1960s and 1970s, These agents were effective in treating psychosis, but were accompanied by significant side effects, including severe parkinsonism and akathisia. Second-generation antipsychotics were introduced in the 1990s, These drugs have at least equal efficacy to their predecessors, but far fewer side effects. Some data suggest a broader efficacy profile. Clozapine remains the only superior antipsychotic in terms of the magnitude of psychotic symptom reduction. Clinical and animal studies are consistent in suggesting that the antipsychotic component of antidopaminergic treatments is initiated by dopamine receptor blockade in the striatum and that the signal is transmitted to the neocortex through the established basal ganglia-thalamo-cortical neuronal circuits. Other neurotransmitter actions (eg, antiserotonergic) can be exerted locally, in the neocortex. Defining tissue targets of drug action may suggest additional strategies for developing new antipsychotic drugs.     

Treatments for chronic psychosis

Psychosis is a mental condition characterized by hallucinations, delusions, and thought disorder; it spans diagnostic entities that respond to similar therapeutic approaches. Psychosis has no fully described tissue pathology, as vet, but is still identified and assessed symptomatically. The first generation of antipsychotic drugs was developed in the middle of the 20th century. The second generation of drugs arrived in the 1990s. This new group of antipsychotic drugs has potent therapeutic actions on the positive symptoms of psychosis with far fewer side effects, especially motor effects. However, each of the new drugs has its own characteristic clinical and pharmacological features that affect individual patient response. Understanding these individual drug characteristics can promote optimal drug choice and use in conditions of chronic psychosis.     

The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia

The US National Institute of Mental Health supported an initiative to facilitate the development of pharmacological agents for enhancing neurocognition in patients with schizophrenia. This has been accomplished through a consensus-building process that has included representatives from academia, the pharmaceutical industry, and government. The group has addressed obstacles to drug development that include (i) the lack of a well-accepted instrument for measuring neurocognition in clinical trials; (ii) the lack of a consensus on the best molecular target or targets for drug development; (iii) the lack of a consensus regarding the optimal trial design for either comedication that improves cognition when added to an antipsychotic or a broad spectrum agent that improves cognition and treats psychosis; and (iv) the approaches of regulatory agencies such as the US Food and Drug Administration to approving and labeling a new agent.     

Early biomarkers of psychosis

Biological traits that are predictive of the later development of psychosis have not yet been identified. The complex, multidetermined nature of schizophrenia and other psychoses makes it unlikely that any single biomarker will be both sensitive and specific enough to unambiguously identify individuals who will later become psychotic. However, current genetic research has begun to identify genes associated with schizophrenia, some of which have phenotypes that appear early in life. While these phenotypes have low predictive power for identifying individuals who will become psychotic, they do serve as biomarkers for pathophysiological processes that can become the targets of prevention strategies. Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia.     

Clinical predictors of therapeutic response to antipsychotics in schizophrenia

The search for clinical outcome predictors for schizophrenia is as old as the field of psychiatry. However, despite a wealth of large, longitudinal studies into prognostic factors, only very few clinically useful outcome predictors have been identified. The goal of future treatment is to either affect modifiable risk factors, or use nonmodifiable factors to parse patients into therapeutically meaningful subgroups. Most clinical outcome predictors are nonspecific and/or nonmodifiable. Nonmodifiable predictors for poor odds of remission include male sex, younger age at disease onset, poor premorbid adjustment, and severe baseline psychopathology. Modifiable risk factors for poor therapeutic outcomes that clinicians can act upon include longer duration of untreated illness, nonadherence to antipsychotics, comorbidities (especially substance-use disorders), lack of early antipsychotic response, and lack of improvement with non-clozapine antipsychotics, predicting clozapine response. It is hoped that this limited capacity for prediction will improve as pathophysiological understanding increases and/or new treatments for specific aspects of schizophrenia become available.     

Differing response to antipsychotic therapy in schizophrenia: pharmacogenomic aspects

Treatment-resistance in schizophrenia remains a public health problem: about 20% to 30% of patients do not respond to antipsychotic therapy. Clozapine has been shown to be effective in about one-third of patients, but the medical risks and weekly blood tests limit its broad application. While the heterogeneity of the disease and the duration of untreated psychosis are important, pharmacogenomic aspects must also be considered. Pharmacogenomic investigations offer the opportunity to individualize antipsychotic therapy according to the growing knowledge of the function and effect of the genetic polymorphisms that affect the pharmacokinetics and pharmacodynamics of antipsychotics. On the pharmacokinetic level, polymorphic phase I and II drug-metabolizing enzymes and transport proteins affect drug concentration at the target structure. The cytochrome P450 enzymes, N-acetyltransferase, and multidrug resistance protein (MDR1) particularly influence this parameter. Genetic alterations affecting drug pharmacodynamic properties have an impact on therapeutic outcome that is generally independent of the applied dosage regimen. A combined analysis of genetic polymorphisms in the dopaminergic and serotonergic receptors, neurotransmitter transporters, and other target structures involved in psychiatric disorders is already a powerful predictor of therapeutic outcome. An understanding of other factors influencing gene expression and protein production will facilitate individualized therapy in the future.     

Quality of life in schizophrenic patients

In the last decades, there has been increased interest in the field of quality of life in mental disorders in general, and particularly in schizophrenia. In addition, the appearance of the atypical antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) with different therapeutic and side-effect profiles, has promoted a greater interest in assessing the quality of life of schizophrenic patients. In this paper we will briefly summarize the difficulties in assessing quality of life in schizophrenic patients, as well as the results concerning their quality of life and the influence of psychopathology, especially negative and depressive symptoms, on it. We will also review data from recent clinical trials showing the impact ofantipsychotic treatments and their side effects upon quality of life.     

Neonatal disconnection of the rat hippocampus: a neurodevelopmental model of schizophrenia

In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizophrenia, including functional pathology in presumably critical brain regions interconnected with the hippocampal formation and targeted by antipsychotic drugs (the striatum/nucleus accumbens and the prefrontal cortex), and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine-related behaviors. Moreover, our data show that even transient inactivation of the VH during a critical period of development, which produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected latematuring regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion.     

Pharmacologic treatment of schizophrenia

Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. 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 has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second-generation antipsychotics. However when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. 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 improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.     

Quantitative analysis of motor disturbances in schizophrenic patients

The presence of neurological signs and disturbed psychomotor performance have been consistently confirmed by clinical studies in schizophrenic patients. These parameters are mainly assessed by using clinical rating scales. In recent years, new approaches such as ultrasonic movement analysis systems have been introduced in order to objectively evaluate motor disturbances in schizophrenic patients. Ultrasonic movement analysis systems calculate the three-dimensional positions of tiny markers, which are attached to moving body parts, with high spatial and temporal resolution. Thus, key parameters of gait and hand movements can be determined precisely. This article summarizes and discusses several studies using these new methods. Results indicate that schizophrenia causes a specific motor deficit pattern, with a predominant disturbance of spatial parameters. Conventional antipsychotic treatment usually worsens these deficits, whereas the effects of atypical antipsychotic treatments are less pronounced. Disturbed motor performance can be normalized by external sensory stimuli, but only when no major attentional processes are required, and it can be enhanced by an attentional strategy, but not to the extent that motor parameters are normalized.     

Neuroimaging biomarkers to predict treatment response in schizophrenia: the end of 30 years of solitude?

Studies that have used structural magnetic resonance imaging (MRI) suggest that individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, and in the white matter tracts that connect them. Furthermore, these studies suggest that brain alterations may be particularly prominent, already at illness onset, in those individuals more likely to have poorer outcomes (eg, higher number of hospital admissions, and poorer symptom remission, level of functioning, and response to the first treatment with antipsychotic drugs). The fact that, even when present, these brain alterations are subtle and distributed in nature, has limited, until now, the utility of MRI in the clinical management of these disorders. More recently, MRI approaches, such as machine learning, have suggested that these neuroanatomical biomarkers can be used for direct clinical benefits. For example, using support vector machine, MRI data obtained at illness onset have been used to predict, with significant accuracy, whether a specific individual is likely to experience a remission of symptoms later on in the course of the illness. Taken together, this evidence suggests that validated, strong neuroanatomical markers could be used not only to inform tailored intervention strategies in a single individual, but also to allow patient stratification in clinical trials for new treatments.     

Studies in schizophrenia: pathophysiology and treatment

Studies on the pathophysiology of schizophrenia have implicated the limbic cortex, using postmortem, structural, and functional data, especially in the hippocampus (HC) and the anterior cingulate cortex (ACC). We have made contributions to the literature consistent with this idea: first, we describe a positive significant correlation between psychotic symptoms in schizophrenia and neuronal activity in the ACC and HC, suggesting the involvement of limbic cortex in the mediation of symptoms in schizophrenia. Second, in the ACC and the anterior HC (but not in the posterior HC), regional cerebral blood flow (rCBF) is abnormal (ie, reduced in the ACC and elevated in the HC) in schizophrenia. Third, the relationship of rCBF to task difficulty in the ACC is altered in schizophrenia, suggesting a failure of participation of the ACC in effortful tasks. Lastly, connectivity between the ACC and HC during the performance of an auditory discrimination task is also lacking, suggesting that cognitive performance in schizophrenia lacks a functional limbic contribution. On the basis of these changes, we studied the effects of antipsychotic drugs in these abnormal areas in persons with schizophrenia. Both first- and second-generation antipsychotics produce functional alterations in these limbic cortical areas, in the direction of normals, putatively acting through the brain's own cortical-subcortical circuits.     

Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia

All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor. Recent meta-analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms. This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic "pathologic circuit" in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia. Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed.     

Future prospects in depression research

Major depression is a common, disabling, and often difficult-to-treat illness. Decades of research into the neurobiology and treatment of depression have greatly advanced our ability to manage this disorder. However, a number of challenges remain. A substantial number of depressed patients do not achieve full remission despite optimized treatment. For patients who do achieve resolution of symptoms, depression remains a highly recurrent illness, and repeated episodes are common. Finally, little is known about how depression might be prevented, especially in individuals at increased risk. In the face of these challenges, a number of exciting research efforts are currently under way and promise to greatly expand our knowledge of the etiology, pathophysiology, and treatment of depression. This review highlights these future prospects for depression research with a specific focus on lines of investigation likely to generate novel, more effective treatment options.     

Can premorbid and prodromal markers associated with psychosis be utilized for early detection and secondary prevention of schizophrenia?

The rationale for identifying markers of latent schizophrenia is the evidence that early treatment speeds remission and lessens long-term deterioration. Unfortunately hovever, although the childhood and adolescence of individual psychotics often reveal premorbid deviations from established norms, while epidemiological studies identify cognitive performance and social adjustment as potential premorbid markers, such signs vary widely and no typical prodrome has been identified. Illness-related events or behaviors are not the only factors precipitating the transition from premorbid to prodrome: educational and socioeconomic status are also involved, it follows that there is a controversy surrounding the secondary prevention of schizophrenia: because of the poor specificity of premorbid and prodromal markers, treating such patients implies thai an unacceptably high proportion of individuals who will not ultimately develop florid schizophrenia will be exposed to stigma of a provisional diagnosis of severe mental illness as well as to the adverse effects of treatment Schizophrenia, therefore, is an aggravated illustration of the dilemmas facing much preventive therapy.     

Antipsychotic dosing and concurrent psychotropic treatments for Medicaid-insured individuals with schizophrenia

Antipsychotic medications have been first line treatment for schizophrenia for half a century, yet few studies have assessed outpatient maintenance treatment in large populations. This article describes oral antipsychotic dosing patterns and psychotropic treatments using computerized Medicaid claims data for individuals who were diagnosed with schizophrenia and received treatment on an outpatient basis during 1991. The findings show that the mean daily oral antipsychotic dose was 729 +/- 586 chlorpromazine equivalents (CPZ-EQ) for high-potency agents and 304 +/- 328 CPZ-EQ for low-potency agents. Males, younger individuals, and African-Americans received larger mean daily doses of high-potency agents, ranging from 747 to 800 CPZ-EQ. Antiparkinsonian agents were prescribed for over 90 percent of the outpatient antipsychotic treatment exposure. In summary, young adults, males, and African-Americans were given high-potency antipsychotic medications at outpatient maintenance doses that exceeded the maximum recommended levels, despite well-established evidence that high-dose treatment offers no additional benefit. Likewise, concurrent antiparkinsonian treatment exceeded the 1990 World Health Organization recommendations.