- 1 Etiology and Pathophysiology
- 1.1 Etiology
- 1.1.1 Genetic Epidemiology
- 1.1.2 Molecular Genetics
- 1.1.3 Environmental Risk Factors
- 1.1.4 Pregnancy and Delivery Complications
- 1.1.5 Childhood and Prenatal Viral Infections
- 1.1.6 Season Of Birth
- 1.1.7 Urban Birth and Residence
- 1.1.8 Psychosocial Factors
- 1.1.9 Models Of Schizophrenia
- 1.1.10 Early Neurodevelopmental Model
- 1.1.11 Late Neurodevelopmental Model
- 1.1.12 Post-Onset Neurodegeneration Model
- 1.1.13 Integrative “Unitary” Models
- 1.1.14 Therapeutic Implications
- 1.2 Pathophysiology
- 1.1 Etiology
- 2 Current Therapies
- 3 Emerging Therapies
- 3.1 Schizophrenia: Serotonin-Dopamine Antagonists
- 3.2 Dopamine Partial Agonists
- 3.3 Schizophrenia: AMPA Receptor Modulators
- 3.4 Glycine NMDA-Associated Agonists
- 3.5 Nicotinic Acetylcholine Agonists
- 3.6 Schizophrenia: Acetylcholinesterase Inhibitors
- 3.7 Schizophrenia: Neurokinin Antagonists
- 4 Related Posts
Etiology and Pathophysiology
Schizophrenia has varied and ominous symptoms that generally begin in late adolescence or early adulthood and usually continue throughout life. The diagnostic criteria for schizophrenia have evolved over the past 20 years based on the different iterations of the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases. The essential concept in both systems is that schizophrenia is expressed through a variety of persistent or chronic mental and behavioral symptoms that cannot be explained as secondary to some other medical or psychiatric condition. Included in both the International Classification of Diseases and Diagnostic and Statistical Manual of Mental Disorders definitions are positive symptoms (such as delusions and hallucinations) and negative symptoms (such as abnormalities in emotional expression or social interaction). In addition to these positive and negative symptoms, patients suffer from an inability to pay attention, the loss of a sense of pleasure, the loss of will or drive, disorganization or impoverishment of thoughts and speech, flattening of affect, and social withdrawal. Cognitive dysfunction, including reduced ability to focus attention and deficiencies in short-term memory, executive functioning, verbal fluency and memory, and motor function, is also a feature of schizophrenia.
Although the etiology of schizophrenia remains to be elucidated, it is well established that both genetic and environmental factors play important roles in the development and clinical manifestation of the disease. Most models of schizophrenia hypothesize that interactions between genetic predisposition and environmental influences disrupt neurodevelopmental processes that lead first to premorbid symptoms and then to the onset and progression of schizophrenia.
Epidemiological studies conducted over the past several decades have demonstrated that schizophrenia is substantially heritable. Perhaps the strongest data in support of a genetic contribution to schizophrenia are the results from studies that show higher concordance rates in monozygotic twins (twins who share 100% of their genetic material) versus dizygotic twins (twins who share 50% of their genetic material). A review of this literature found that monozygotic twins of persons with schizophrenia have a 53% chance of developing the disorder, while dizygotic twins of affected persons have only a 15% chance of developing schizophrenia. That monozygotic twins are three times more likely to display concordance than dizygotic twins provides persuasive evidence of genetic influence. However, these findings also illustrate the importance of environmental factors: because the concordance in monozygotic twins is not 100%, nongenetic factors must have etiological significance.
Despite the wealth of evidence supporting a genetic basis of schizophrenia, the precise pattern of inheritance has not been clearly delineated. Findings from pedigree studies suggest genetic transmission of schizophrenia within families, but these results cannot be explained by the inheritance of a single major gene. Instead, these studies point strongly to a multifactorial model, whereby the effects of multiple genes and environmental factors combine to increase disease liability.
Because of schizophrenia’s complex inheritance pattern, identifying and characterizing genes that confer risk for the disorder have proved extremely difficult. However, advances in molecular genetic technologies have made it increasingly feasible to investigate the genetic underpinnings of schizophrenia. Molecular genetics is the study of the flow and regulation of genetic information between DNA, RNA, and protein molecules. By isolating disease-conferring genes, researchers hope to identify and directly study the root causes of the disease. Such insights may have a profound impact on the development of more rational and efficacious agents for the treatment of schizophrenia as well as the development of primary prevention initiatives.
Studies have reported significant linkage to several genomic regions and have inspired renewed confidence in the applicability of molecular genetic methods to the study of psychiatric illness. Of particular interest is a study that used linkage and fine-mapping techniques to identify neuregulin 1 as a candidate gene for schizophrenia. The authors also show that mice harboring a mutant form of neuregulin 1 (or its receptor ErbB4) exhibit behavioral abnormalities that are consistent with animal models of schizophrenia and that are partially reversed by administration of the antipsychotic clozapine. Notably, neuregulin 1 has a clear role in the expression and activation of neurotransmitters, including glutamate, a focus of current research on schizophrenia pathophysiology. The catechol-O-methyl transferase gene has also emerged as a candidate risk factor for schizophrenia. The gene has attracted considerable interest because it resides within a well-replicated linkage region at the ql 1 band of chromosome 22 and it encodes one of the key enzymes involved in the degradation of catecholamines, including dopamine. A study found a strong association between several catechol-O-methyl transferase haplotypes and schizophrenia in a population of Ashkenazi Jews. This finding is one of the most statistically significant results ever reported for a common disease with a complex inheritance pattern. The catechol-O-methyl transferase gene also contains a functionally relevant single nucleotide polymorphism that apparently influences the enzyme’s metabolic activity. The high-activity form of this polymorphism was shown to be associated with cognitive characteristics that are present in schizophrenia — namely, poor performance in tests assessing frontal lobe function and reduced brain activity in the pre-frontal cortex. In light of these findings, the National Institutes of Mental Heath, a division of the National Institutes of Health (NIH), is conducting trials to determine whether tolcapone, a catechol-O-methyl transferase inhibitor used to treat Parkinson’s disease, can improve cognitive performance in schizophrenic patients with different catechol-O-methyl transferase genotypes. Although this avenue of research is interesting, tolcapone likely will not launch for the treatment of schizophrenia because of its potential to elevate hepatic transaminase blood levels (detected in up to 3% of trial subjects), a situation that can lead to liver failure. This rare but serious hepatic adverse event led to the suspension of tolcapone’s marketing for Parkinson’s disease.
Several genome scans have implicated a potential link between chromosome 15 (which is host to the a 7 nicotinic receptor) and the etiology of schizophrenia. Although some studies have failed to confirm this linkage, there are significant linkage reports from studies of German, European, U.Spain., Azorean, and Taiwanese families. In response to this research, several companies have begun pursuing drugs that modulate the a 7 nicotinic receptor for the treatment of cognitive-dysfunction-associated schizophrenia. One such agent reached Phase II trials but was recently suspended for unknown reasons.
Another interesting avenue that has spawned drug development is the identification of the novel schizophrenia-associated gene, G72, which is located at chromosome 13q22-34 and encodes the 153-amino-acid protein pLG72. Yeast two-hybrid experiments identified the enzyme D-amino-acid oxi-dase (DAAO) as an interacting partner for pLG72. DAAO oxidizes D-amino acids including D-serine, an endogenous modulator of N-methyl-d-aspartate receptor function. These data further support the role of N-methyl-d-aspartate and glutamate in general in the etiology and pathophysiology of schizophrenia and have spurred interest in the development of drugs that modulate glutamate, such as AMPA modulators, glycine N-methyl-d-aspartate-associated agonists, and N-methyl-d-aspartate modulators. Initial clinical data have shown that drugs that modulate glutamate modestly improve cognition and negative symptoms.
Environmental Risk Factors
The evolving perspective of schizophrenia experts is that a genetic predisposition may leave a person vulnerable to certain environmental events that trigger the onset of this disease. Such environmental factors include biological, physical, and psychosocial events that the person experiences from conception through prenatal development, birth, and subsequent development. However, the interplay of genetic and environmental factors in the development of schizophrenia remains poorly understood and may be very complex. For example, environmental factors may have different effects on different people, depending on their particular genotypic predisposition to the illness. Investigations have implicated several environmental influences that likely play a role in the development of schizophrenia.
Pregnancy and Delivery Complications
A variety of pregnancy and delivery complications have been associated with the risk of schizophrenia in later life. In one study, children who suffered complications — identified by low Apgar scores indicative of fetal hypoxia, neonatal convulsions, asphyxia, or abnormal neurological signs — were at sevenfold higher risk for developing schizophrenia than children with no indication of perinatal brain damage. Furthermore, some researchers suggest an increased risk of schizophrenia is linked to exposure to infections during the second trimester, maternal stress, and nutritional deficiencies in utero. Studies have also shown, however, that most people whose birth is characterized by obstetric complications do not become schizophrenic, suggesting that those who do develop schizophrenia have a genetic predisposition that confers heightened sensitivity to the neurotoxic effects of early brain insults.
Childhood and Prenatal Viral Infections
Other data indicate that people who had a childhood viral infection of the central nervous system are approximately five times more likely than the control cohort to develop schizophrenia. The risk associated with viral infections may be related to maternal viral infections as well. Viral infections during the second trimester of pregnancy, in particular, have been proposed as a precursor to schizophrenia. According to this hypothesis, the mother passes the virus to the embryo, thereby affecting brain development. However, to date, no single type of virus has been identified as a primary causative agent. Influenza, once a suspect, is now thought to be a risk factor of relatively modest proportion.
Season Of Birth
Birth during winter months is associated with higher rates of schizophrenia. Eighteen of 19 large North American studies showed a 5-8% excess of births of people who eventually developed schizophrenia (and other psychiatric disorders) during December through May, with peaks in January and February. Researchers hypothesize that higher rates of schizophrenia in the winter months may be the result of higher rates of infectious diseases, although not all studies have confirmed this association.
Urban Birth and Residence
The prevalence of schizophrenia is higher in urban areas than in rural areas, suggesting that people in urban areas are at higher risk to develop schizophrenia. For example, in a large study in the Netherlands, schizophrenia and other psychoses were found to correlate with urban births, increasing with population density. Similar findings were reported in a Danish study that showed the risk of schizophrenia among people living in a capital is more than twice that of people living in a rural area.
One study found that adoptees at increased genetic risk of developing schizophrenia (e.g., adoptees with schizophrenic birth mothers) are more likely to develop schizophrenia if exposed to dysfunctional family environments. This association, however, was not observed in control adoptees with no family history of the disorder.
Models Of Schizophrenia
Efforts to explain the etiology of schizophrenia have focused on three models, each based on different facets of the disorder. These hypotheses have also spawned integrative models that incorporate all three mechanisms. In general, the current prevailing view is that schizophrenia is a neurodevelopmental disorder in which structural brain changes, caused by an early prenatal or perinatal insult, confer a predisposition to the development of schizophrenia. However, researchers still debate whether schizophrenia results simply from abnormal development or whether additional neurodegenerative processes are initiated at, or shortly before, the onset of psychosis.
Early Neurodevelopmental Model
This model assumes that schizophrenia is a neurodevelopmental disorder in which the primary pathological process occurs during the early stages of brain development, long before the illness manifests itself clinically. Evidence cited in support of this model includes findings of increased risk of schizophrenia associated with complications of pregnancy and delivery (e.g., perinatal hypoxia) and viral infections early in life, clinical findings of cognitive deficits dating back to early childhood in schizophrenic patients, and neuropathological findings of altered cytoarchitecture, possibly caused by aberrations in programmed cell death, neural migration, and/or synaptic proliferation, processes that begin during the second trimester of pregnancy.
Late Neurodevelopmental Model
Proponents of this theory argue that schizophrenia results from abnormalities in the late neurodevelopmental processes that occur during adolescence — in particular, synaptic pruning and myelination. Evidence suggests that the normal process of synaptic pruning, which occurs during periadolescence, is exaggerated in particular brain regions (e.g., the prefrontal cortex) in schizophrenics. This exaggeration may lead to reduced cortical synapse density and plasticity, which could affect the brain’s ability to mediate and respond to stress.
Post-Onset Neurodegeneration Model
This model proposes that neurode-generative changes beginning in early adulthood cause or exacerbate schizophrenia. Clinical correlates include the findings that disease progression may be arrested by early therapy with antipsychotic agents (a strategy under evaluation in clinical trials), that longer duration of untreated illness correlates with a poorer outcome, and that recovery is slower and less complete over successive episodes. Although this model is the least accepted as a complete explanation for the pathophysiology of schizophrenia, aspects of it may play a role in combination with other mechanisms.
Integrative “Unitary” Models
Researchers have also developed models of the pathophysiology of schizophrenia that integrate the evidence supporting each of the hypotheses discussed in the preceding sections. Many researchers suggest that changes in excitatory amino acid neurotransmitters — particularly glutamate, the predominant excitatory amino acid of the central nervous system — may underlie the various pathophysiological stages of schizophrenia.
Researchers theorize that multiple genes and environmental factors produce various pathological defects typically seen in the brains of schizophrenics, such as the anatomical and neurochemical disturbances. More specifically, these abnormalities could result from disruptions to the mechanisms that govern neurodevelopmental processes, such as cellular proliferation and differentiation, axonal outgrowth, and synaptic regression.
Three of the previously discussed hypotheses relate to a clinical stage (premorbid, onset, and post-onset), suggesting that different mechanisms may be involved at different stages of disease development. Future therapies for schizophrenia could be based on the following key strategies:
• Use of the right drug for the specific mechanism at each stage of disease development.
• Administration at the right time — that is, at the proper stage.
• Selection of the “right patient” — that is, personalizing drugs to the specific mechanisms involved in individual patients, based on genotype (which will predict mechanisms) and/or pathophysiological findings (assuming advances in imaging or other diagnostic/prognostic methodologies).
Finally, an integrative or unified theory may explain all or many of the various, seemingly unrelated findings that occur at various stages of the disease. The theory that glutamate may underlie all of the pathophysiological stages of schizophrenia is one possibility; however, it is unclear whether this explanation adequately accounts for the full range of pathophysiological changes associated with schizophrenia.
If the neurodevelopmental hypotheses prove valid and more is learned about the interplay, early in life and in adolescence, of genetic and environmental factors that predispose individuals to schizophrenia, new generations of drugs could eventually be designed not only to improve treatment of schizophrenia but to prevent its occurrence altogether.
The symptoms of schizophrenia are associated with dysfunction of several neurochemical systems, many of which are the targets of current and emerging antipsychotic therapies and are discussed in the following sections. Table Key Symptoms of Schizophrenia briefly describes some of the more common signs and symptoms of schizophrenia. Table Receptor-Binding Affinities of Select Antipsychotics displays the receptor-binding profiles of select atypical agents.
The classical dopamine hypothesis of schizophrenia proposes that excessive dopamine neurotransmission in the limbic system (i.e., the inner region of the brain involved in emotion and memory) correlates with the manifestation of positive psychotic symptoms (e.g., delusions, hallucinations). In the past, this hypothesis was supported primarily by indirect pharmacological evidence. More recently, the development of sophisticated neuroimaging techniques has provided more direct substantiation of the role of this dopaminergic dysfunction in positive symptom formation.
TABLE: Key Symptoms of Schizophrenia
|Positive symptoms||Include distortions or exaggerations of inferential thinking (delusions), perception (hallucinations), language and communication (disorganized speech), and behavioral monitoring (grossly disorganized or catatonic behavior). Markedly incoherent speech and disorganized and agitated behavior occur without apparent awareness on the part of the patient of the incomprehensibility of his behavior. These psychotic symptoms may comprise two distinct dimensions, which may in turn be related to different underlying neural mechanisms and clinical correlations: the “psychotic dimension” includes delusions and hallucinations, whereas the “disorganization dimension” includes disorganized speech and behavior.|
|Negative symptoms||Include restrictions in the range and intensity of emotional expression (affective flattening), in the fluency and productivity of thought and speech (alogia), and in the initiation of goal-directed behavior (avolition). These symptoms usually result in social withdrawal and lowering of social performance. They are not due to depression or to antipsychotic medication. Primary negative symptoms are thought to reflect an inherent component of the illness, whereas secondary negative symptoms result from other factors (e.g., poorly controlled psychotic symptoms, antipsychotic-induced extrapyramidal symptoms, institutionalization).|
|Cognitive dysfunction||Includes distractibility, impaired insight, and lack of recognition. The cognitive functions that may be impaired include verbal memory, executive functioning, attention, motor speed, visuospatial capacity, and verbal fluency. Poor cognitive function reduces the likelihood that a patient will be able to understand, remember, and cooperate with pharmacological or behavioral treatment regimens.|
TABLE: Receptor-Binding Affinities of Select Antipsychotics
First, increased subcortical dopamine turnover has been demonstrated in drug-naive schizophrenic patients using positron emission tomography. Second, in studies using an imaging technique that measures the release of dopamine in mesolimbic areas, an amphetamine challenge was shown to enhance this release significantly more in drug-naive schizophrenic patients than in control subjects. Furthermore, this elevation appears to correlate with the induction of positive symptoms. Thus, there is evidence that both baseline dopamine neurotransmission and stimulated release of dopamine are abnormal in mesolimbic systems of the schizophrenic brain.
Hyperactivity of dopaminergic synapses also produces abnormalities in sensory gating, a mechanism that prevents excessive sensory stimulation. Sensory gating abnormalities are an early clinical symptom of schizophrenia. These abnormalities may account for the confused thought processes of psychotic patients.
In addition, some evidence suggests that the severity of negative symptoms (e.g., affective flattening, avolition) correlates with hypodopaminergic activity in the cortical system (i.e., the outer region of the brain involved in communication and cognition). For example, imaging of the brains of schizophrenic patients experiencing negative symptoms revealed reduced blood flow and reduced metabolic activity (e.g., glucose uptake and utilization) in the prefrontal cortex, an area innervated by the mesocortical system and involved in making associations between stimuli and deciding how to respond to them.
Given the hypotheses stating that schizophrenia can be traced to the dopamine system, intensive research efforts have been devoted to elucidating the possible neurochemical dysfunctions of dopamine and its receptors. Two families of dopamine receptors exist in the brain:
• The D1 family (D1 and D5 receptors).
• The D2 family (D2, D3, and D4 receptors).
Other dopamine receptors remain to be characterized.
With respect to schizophrenia, the classical dopamine hypothesis has traditionally centered on the role of D2 receptors because partial blockade of these receptors correlates with the therapeutic efficacy of antipsychotics. Nevertheless, the relationship between D2 receptor occupancy and clinical effect is not straightforward. Brain-imaging studies using single-photon emission computerized tomography (SPECT) reveal no difference in striatal D2 receptor availability between responders and nonresponders to antipsychotic medication, suggesting that the D2 receptor is not the sole relevant target for antipsychotic medications.
Analysis of the specificity and affinity of antipsychotic medications has shown that these agents target a variety of dopamine receptors. Some researchers suggest that some atypical and typical antipsychotics may exert part of their antipsychotic effect via their action on D3 dopamine receptors. However, some atypical agents, most notably risperidone (Janssen’s Risperdal), have little or no affinity for D3 receptors. Studies have shown increased D3 receptor subtypes in the limbic system of some schizophrenic patients, but follow-up studies are needed to explain this finding.
Interest in the role of D4 receptors was spurred by clozapine’s (Novartis’s Clozaril/Leponex) efficacy in treating patients whose disease has proved refractory to other antipsychotics. Clozapine is a D4 antagonist that acts on a multitude of other receptors. However, enthusiasm has been tempered by data suggesting selective D44 antagonists are ineffective antipsychotics. Scant research data exist to explain the pathophysiological role of Di and D5 receptors.
Serotonin has been implicated in a variety of schizophrenia symptoms, such as hallucinations, cognitive dysfunction, sensory gating, and aggression. The discovery that the atypical antipsychotics have relatively high affinity for serotonin 5-НТ2 receptors has engendered intense interest in the role of this receptor class in the etiology and treatment of schizophrenia. Specifically, researchers hypothesize that the relative lack of extrapyramidal symptoms — a characteristic that differentiates atypical from typical antipsychotics — results from the high occupancy of 5-HT2 receptors at doses that produce partial occupancy of D2 receptors.
The first systematic study using positron emission tomography brain imaging to compare D2 and 5-НТ2 receptor occupancy indicated that the atypical drugs clozapine, olanzapine, and risperidone all fully occupied 5-НТ2 receptors at doses well below those required to produce antipsychotic action. This finding suggests that either 5-НТ2 occupancy is not in itself sufficient to initiate antipsychotic action or that antipsychotic action may require a very low level of unoccupied receptors. The consensus is that the superiority of atypical drugs relative to the typical agents results from the former’s dual occupancy of dopamine and serotonin receptors. Indeed, the blocking of the serotonin receptors may be a requirement for the reduction in extrapyramidal symptoms that is characteristic of the atypical agents. Specifically, 5-НТ2B blockade in the nigrostriatal pathway may reduce the effect of D2 receptor blockade that is responsible for causing extrapyramidal symptoms.
A convergence of evidence suggests that alterations in levels of gamma-aminobutyric acid, the major inhibitory neu-rotransmitter, play an important role in the pathophysiology of schizophrenia. Numerous postmortem investigations have demonstrated that the activity of glutamic acid decarboxylase, the enzyme responsible for gamma-aminobutyric acid synthesis well as the uptake and release of gamma-aminobutyric acid, is markedly reduced in the brains of schizophrenic patients. Studies have also shown a selective reduction in messenger RNA (mRNA) expression of glutamic acid decarboxylase in the prefrontal cortex; this area of the brain is thought to be of fundamental importance to psychotic symptom production and the pathophysiology of schizophrenia. Researchers suggest that activation of the GABAA receptor may be efficacious in treating the positive and, to a lesser degree, negative symptoms of schizophrenia.
Glutamate, an excitatory amino acid that activates N-methyl-d-aspartate receptors in the brain, is known to be involved in neurode-velopment, neurotransmission, and neurotoxicity. Agonists of N-methyl-d-aspartate receptors, such as phencyclidine (“angel dust”), produce a psychotic state that bears a striking resemblance to some of the symptoms of schizophrenia and bipolar disorder. Also, mice carrying a targeted mutation in the gene for the NR1 subunit of the N-methyl-d-aspartate receptor assembly (which is crucial for normal receptor function) display abnormalities in social behavior that are ameliorated by clozapine treatment. Not surprisingly, given this evidence, researchers have been attempting to determine whether an endogenous deficiency of glutamatergic transmission mediated by N-methyl-d-aspartate receptors could be involved in the pathophysiology of psychotic disorders.
Researchers suggest that in the normal brain, the amount of sensory input allowed to reach the cerebral cortex is restricted by an inhibitory effect of the striatal complexes on the thalamus. This effect protects cortical neurons receiving sensory input from being overwhelmed. Evidence supports the idea that a weakened glutamatergic tone in the brains of schizophrenics upsets a balance between glutamatergic and dopaminergic transmission. This imbalance may then predispose those persons to a risk of sensory overload and exaggerated responsiveness of the monoaminergic systems, which could lead to the onset of psychosis.
Drugs that stimulate N-methyl-d-aspartate receptors may be a viable class of agents for the treatment of psychotic disorders. Provocative preliminary clinical trial results are fueling interest in this concept. Companies are investigating various compounds that interact in different ways with the glutamatergic system. Examples are the glycine N-methyl-d-aspartate-associated agonists, glycine reuptake inhibitors, and AMPA modulators. Aggregate, preliminary results from these studies suggest that these compounds may reduce primary negative symptoms and cognitive deficits in patients with schizophrenia. For more information, see “Emerging Therapies,” which discusses these therapeutic approaches in more detail.
Abnormalities in Brain Structure and Function
A wealth of evidence from postmortem and in vivo neuroimaging studies has shown that schizophrenia is associated with various structural and functional brain abnormalities, including enlarged ventricles (the cerebrospinal-fluid-filled spaces in the brain), reduced regional cerebral (cortical and subcortical) volumes, and reduced activity in the temporal lobes. With existing imaging methods, these abnormalities are not so dramatic as to enable differential diagnosis or prediction of who will develop the disorder later in life, but the link between these abnormalities and schizophrenia is robust and statistically significant.
Studies using high-resolution magnetic resonance imaging have consistently found bilateral reductions in frontal and temporal-limbic gray matter volumes in patients with schizophrenia. These volume deficits have been shown in both chronic and first-episode patient samples, suggesting they are not (solely) the result of a long-standing disease process or its treatment. Instead, these structural brain deficits may predate the onset of the illness and represent a marker of vulnerability for developing schizophrenia. In fact, some unaffected biological relatives of schizophrenia patients demonstrate qualitatively similar but quantitatively milder structural brain abnormalities than those found in schizophrenic family members.
Postmortem morphometric studies are generally consistent with the magnetic resonance imaging literature and have further indicated that frontal volume reduction reflects a loss of interneuronal neuropil (i.e., reduced dendritic and axonal arborization) rather than neuronal cell loss. A likely functional implication of this neuropil deficit is a reduction of connectivity between the prefrontal cortex and other cortical and subcortical brain regions. This disturbed connectivity may underlie some of the symptoms and cognitive deficits of schizophrenia.
Positron emission tomography and functional magnetic resonance imaging studies have also provided evidence of aberrant neural connectivity in schizophrenia. Data from these studies suggest that the pathophysiology of schizophrenia reflects an abnormal amount and integration of brain activity across various cortical, limbic, and subcortical structures, most notably the prefrontal cortex. For example, there is consistent evidence that chronic and first-episode schizophrenic patients fail to activate the prefrontal cortex to the degree seen in healthy volunteers when performing tests of abstract reasoning, verbal fluency.
It is likely that brain imaging techniques, coupled with new information on genetically defined risk factors, will eventually shed light on the mechanisms involved in the development of schizophrenia. Future drug development may rely on the convergence of genetic and clinical trial data, together with the use of brain imaging studies and traditional neuropharmacological approaches, to define an optimal product profile for a new generation of antipsychotic agents. Eventually, such integrative approaches may help identify people who are at greater risk for developing schizophrenia and who would benefit from prophylactic pharmacological intervention. This area is the subject of intense investigation and one with dramatic implications for the design and implementation of therapeutic interventions.
Two kinds of antipsychotics are available: typical and atypical. In this section, the term atypical antipsychotic refers to antipsychotics that block 5-HT2A receptors as well as D2 receptors and are associated with a low risk of movement disorders; the term typical antipsychotic refers to antipsychotics that have relevant affinities for the D2 receptor but are largely devoid of affinities for 5-HT2A receptors and are associated with a higher risk of movement disorders.
Atypical agents offer benefits in terms of efficacy and tolerability over typical antipsychotics. All antipsychotics are generally similar in their ability to reduce the positive symptoms of schizophrenia (e.g., delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior). Atypical agents, however, appear more effective than typical agents in addressing negative symptoms (e.g., affective flattening, alogia, avolition). Furthermore, data indicate that patients taking atypical agents may experience better cognitive function than those on typical antipsychotics, though evidence in this regard is not conclusive. Finally, atypical antipsychotics provide advantages over typical antipsychotics with regard to adverse side effects. In particular, the former agents are associated with far fewer drug-induced movement disorders — extrapyramidal symptoms such as parkinsonism and akathisia — and are probably less likely to cause the serious movement disorder tardive dyskinesia (tardive dyskinesia). Table Leading Current Therapies Used for Schizophrenia summarizes the leading therapies available to treat schizophrenia. Table General Properties of Antipsychotic Agents compares the general properties of atypical versus typical antipsychotics. Table Relative Side-Effect Profiles of Select Antipsychotics compares the side-effect profiles of select atypical and typical antipsychotics.
TABLE: Leading Current Therapies Used for Schizophrenia
|Clozapine||Novartis’s Clozaril / Leponex, generics||150-200 mg bid||US, France, Germany,Italy, Spain, United Kingdom|
|Risperidone||Janssen’s Risperdal||2-3 mg bid||US, France, Germany, Italy, Spain, United Kingdom, Japan|
|Risperidone depot||Janssen’s Risperdal Consta||25 mg biweekly||US, Germany, Spain, United Kingdom|
|Olanzapine||Eli Lilly’s Zyprexa||10-15 mg qd||US, France, Germany,Italy, Spain, United Kingdom, Japan|
|Olanzapine intramuscular||Eli Lilly’s Zyprexa||10 mg||United Kingdom|
|Quetiapine||AstraZeneca’s Seroquel||150-200 mgbid||US, Germany, Italy, Spain,United Kingdom, Japan|
|Ziprasidone||Pfizer’s Geodon / Zeldox||40-80 mg bid||US, Germany, Spain|
|Ziprasidone intramuscular||Pfizer’s Geodon / Zeldox||10-40mg||US, Germany, Spain|
|Aripiprazole||Otsuka Pharmaceutical / Bristol-Myers Squibb’s Ability||10-15 mg qd||US|
|Haloperidol||Ortho-McNeil’s Haldol, Dainippon’s Serenace, generics||5 mg bid||US, France, Germany,Italy, Spain, United Kingdom, Japan|
|Haloperidol intramuscular||Ortho-McNeil’s Haldol, Dainippon’s Serenance, generics||2-10 mg||US, France, Germany,Italy,Spain, United Kingdom, Japan|
|Haloperidol decanoate||Ortho-McNeil’s Haldol Decanoate, generics||50-100 mg monthly||US, France, Germany,Italy, Spain, United Kingdom, Japan|
bid = Twice daily; qd = Once daily.
TABLE: General Properties of Antipsychotic Agents
|Property||Atypical Antipsychotics||Typical Antipsychotics|
|Relief of positive symptoms||Yes||Yes|
|Relief of negative symptoms||Yes, to a greater degree than typical antipsychotics; debate is ongoing whether atypicals treat primary or reduce secondary negative symptoms||Yes, to a small degree; typical antipsychotics cause secondary negative symptoms that prevent true evaluation of their effect on primary negative symptoms|
|Extrapyramidal symptoms||Reduced or negligible at recommended doses||Major side effect|
|Tardive dyskinesia||Reduced or negligible at recommended doses||Major side effect|
|Prolactin-related side effects||Reduced or none||Yes|
|Compliance with pharmacotherapy||Evidence that it is increased but evidence not conclusive||Expert consensus is that side effects and poor efficacy against negative symptoms contribute to poor compliance|
|Relief of depression||Some evidence but not conclusive||No|
|Effect on cognition||Positive evidence but not conclusive||Probably not|
TABLE: Relative Side-Effect Profiles of Select Antipsychotics
|PO||PO, D||PO, intramuscular||PO||PO, intramuscular||PO||PO, intramuscular, D|
|extrapyramidal symptoms||+ /-||+ +||+||+ /-||+||+ /-||+ + +|
|Tardive dyskinesia||+ /-||+ /-||+ /-||N.R.||N.R.||+ /-||+ +|
|Prolactin elevation||–||+ + +||+ /-||–||+||–||+ + +|
|Weight gain||+ + +||+ +||+ + +||+ +||+ /-||+ /-||+ /-|
|Glucose elevation||+ + +||+ +||+ + +||+ +||N.R.||+ /-||+ /-|
|Triglyceride elevation||+ + +||+ +||+ + +||+ +||+ /-||+ /-||–|
|Orthostatic hypotension||+ + +||+||+||+ +||+||+||+ /-|
|QTc prolongation||+ /-||+||+ /-||+ /-||+ +||–||+ /-|
|Sedation||+ + +||+||+ +||+ +||–||+||+ +|
|Antic holinergic(5)||+ + +||+ /-||+ +||+ /-||+ /-||+ /-||+ /-|
|Sexual dysfunction||+ /-||+ +||+||+ /-||N.R.||N.R.||+|
Includes dry mouth, blurred vision, urinary hesitation, constipation, learning and memory impairment, confusion, and delirium.
D = Intramuscular long-acting (depot) formulation; IM = Intramuscular short-acting formulation; N.R. = Not reported; PO = Oral.
The atypical antipsychotics are discussed in greater detail than the typical antipsychotics because the atypical agents are becoming the global standard of therapy and the subject of clinical research. Although typical antipsychotics remain important in clinical practice and are used widely outside the United States, they are the subject of few new trials, and no new drugs are in development.
The benefits of treatment with typical antipsychotics include a reduction in positive symptoms and assaultive behavior and better management of severe agitation. Typical antipsychotics are effective in treating positive symptoms in 70-80% of schizophrenic patients. However, as noted earlier, they are only marginally effective against negative symptoms and cognitive dysfunction, and they carry serious adverse side effects such as extrapyramidal symptoms, tardive dyskinesia, and hyperprolactinemia. extrapyramidal symptoms and tardive dyskinesia arise in as many as 75% and 25% of patients treated with typical antipsychotics, respectively. The discomfort associated with extrapyramidal symptoms forces many patients to discontinue therapy.
Many typical antipsychotics are available. This section profiles the most commonly used typical agent — haloperidol (Ortho-McNeil’s Haldol, Dainippon’s Serenace, generics). Other popular typical agents include bromperidol (Welfide’s Hordazol, Janssen’s Impromen), fluphenazine (BMS/Sanofi-Synthelabo’s Prolixin/Dapotum/Moditen, Yoshitomi’s Flumezin, generics), and zuclopenthixol (Lundbeck’s Clopixol, generics).
Mechanism Of Action
Unlike atypical antipsychotics, typical agents block both the limbic and striatal D2 receptors with relatively equal potency. Researchers surmise that D2 blockade is necessary for an antipsychotic effect because no effective antipsychotics are devoid of this property. However, as mentioned earlier, dopamine deficiency in the nigrostriatal pathway can cause extrapyramidal symptoms, while hyperactivity of dopamine in the mesolimbic pathways is thought to cause psychosis. The binding of these typical agents to dopamine receptors within the mesolimbic system appears to account for their favorable effects on positive symptoms, but their binding to dopamine receptors outside the mesolimbic system is the most likely cause of their unwanted motor side effects.
Like the atypical antipsychotics, many typical agents are available in alternate formulations such as orally disintegrating tablets, oral solutions, intramuscular formulations, and long-acting depot formulations. These formulations are intended to ensure compliance in uncooperative or extremely noncom-pliant patients and help physicians provide rapid therapy in emergency situations.
Haloperidol (Ortho-McNeil’s Haldol, Dainippon’s Serenace, generics) is one of the most widely used typical antipsychotics for the treatment of schizophrenia. In 1957, Janssen submitted it to clinical trials in Belgium. Its development was subsequently discontinued as a result of side effects, but the agent was later approved in the United States, Europe, and Japan for the treatment of schizophrenia. In addition to its tablet form, the drug is available in an oral solution, a short-acting intramuscular formulation, and a depot formulation (generically called haloperidol decanoate). Haloperidol is also approved for the control of tics and vocal utterances of Tourette’s disorder.
Haloperidol has strong affinity for D2 and α1-adrenergic receptors and shows no or few interactions with other neurotransmitter receptors. Researchers surmise that D2 blockade is necessary for an antipsychotic effect because no effective antipsychotics are devoid of this property. Haloperidol blocks both limbic and striatal D2 receptors with relatively equal potency. Although the blockage of dopamine in the limbic areas appears to account for haloperidol’s favorable effects on positive symptoms, its unwanted motor side effects are most likely caused by binding to dopamine receptors outside the mesolimbic system.
Haloperidol was launched in the late 1950s and the drug has years’ worth of data and clinical experience demonstrating its efficacy in the treatment of schizophrenia. For example, a small, 14-week, placebo-controlled, double-blind study enrolled 24 chronic schizophrenic male patients. These patients were randomized to receive either placebo, 6 mg of haloperidol, or 30 mg of haloperidol. At the end of the study, treatment with haloperidol resulted in significant improvements in symptoms as measured by the Inpatient Multidimensional Psychiatric Scale (IMPS) and psychiatric evaluation of behavioral changes.
Haloperidol is associated with a side-effect profile similar to that of other typical antipsychotics. It is associated with a high rate of extrapyramidal symptoms; as many as 60% of patients undergoing acute treatment with the drug develop acute dystonia (dyskinetic movements due to disordered tonicity of muscle). It also has the propensity to cause hyperprolactinemia, weight gain ( > 5 kg gain within two months in the average patient), sedation, seizures, neuroleptic malignant syndrome, tardive dyskinesia, sexual dysfunction, and orthostatic hypotension, and it can impair cognitive function.
Over the next ten years, the continued development of atypical antipsychotics will no longer remain the most likely driver for improving the management of schizophrenia. Currently available antipsychotics adequately treat positive symptoms — although some room for improvement exists in tolerability — and future treatment for this disorder will most likely involve an antipsychotic plus additional drugs. Therefore, the treatment of schizophrenia is expected to become fragmented: most patients will receive multiple therapies for various symptoms or sets of symptoms of schizophrenia (e.g., positive symptoms, negative symptoms, cognitive dysfunction).
Overall, an estimated 70 compounds are in development for the treatment of schizophrenia and/or its related symptoms. Most of these compounds are in early-stage development, as illustrated in Figure 8. Based on historical trends, the probability of approval for drugs in clinical development (i.e., Phase I to Phase III) for schizophrenia is 30-39%, meaning that approximately two-thirds of all compounds in clinical development for schizophrenia are typically discontinued. This probability of approval is similar to that of other psychiatric indications.
Emerging therapies are associated with a variety of novel mechanisms, ranging from neurokinin antagonism to glutamate receptor modulation. Figure 9 indicates the relative maturity of the development of the novel drug mechanisms being investigated. The discussion here focuses on those drug mechanisms that have progressed the furthest in clinical trials and on those that have generated the most interest: serotonin-dopamine antagonists, dopamine partial agonists, AMPA receptor modulators, neurokinin antagonists, nicotinic acetylcholine agonists, acetylcholinesterase inhibitors, and glycine N-methyl-d-aspartate-associated agonists. (Glycine reuptake inhibitors are in preclinical development and are expected to address negative symptoms and/or cognitive dysfunction; they are not discussed further in this section.) Table Emerging Therapies in Development for Schizophrenia summarizes drug therapies in development for schizophrenia.
Dopamine Partial Agonists
The launch of aripiprazole (Otsuka Pharmaceutical/Bristol-Myers Squibb’s Abilify) in November 2002 in its first market (United States) has fueled interest in the development of dopamine partial agonists — drugs that can modulate dopamine levels without completely blocking dopamine receptors. In theory, such compounds have the capacity to stabilize dopamine function by performing as antagonists in conditions of neurotransmitter hyperactivity and as agonists in states of hypoactivity. According to clinical data, aripiprazole is as efficacious as other atypical antipsychotics but causes less significant side effects, such as weight gain, hyperglycemia, hyperlipidemia, hyperprolactinemia, and metabolic side effects.
Mechanism Of Action
Dopamine partial agonists’ distinguishing characteristic is their mechanism of action. These drugs are partial agonists at dopamine D2 receptors and can act as dopaminergic stabilizers, performing as dopamine antagonists in conditions of dopamine hyperactivity and exhibiting dopamine agonist properties in states of hypoactivity. Such a profile may offer efficacy against the positive symptoms of schizophrenia while causing fewer dopamine-related side effects, most notably extrapyramidal symptoms and hyperprolactinemia.
Solvay Pharmaceutical/H. Lundbeck’s bifeprunox (DU-127090) could potentially be the second dopamine partial agonist to market. It is in Phase III trials for schizophrenia in the United States and Europe. The drug is also being developed in Japan. In December 2000, Solvay licensed from Lundbeck the development and marketing rights to bifeprunox in the United States, Canada, Mexico, and Japan. Lundbeck has marketing rights in Europe and the rest of the world. Solvay and Lundbeck will jointly market the product in Brazil and Argentina. In April 2004, Solvay and Wyeth Pharmaceuticals announced a development and marketing agreement for bifeprunox in the United States, Canada, Mexico, and Japan. Lundbeck retains rights in Europe and other markets and expects to market this product in 2007.
Like aripiprazole, bifeprunox acts as a dopamine D2 and 5-HT1a partial agonist. Its affinity for D2 receptors is comparable to that of haloperidol and risperidone and superior to that of clozapine and olanzapine. The drug also has a high affinity for D3 and D4 receptors. Like aripiprazole, bifeprunox has a partial agonist effect at 5-HT1a receptors and no affinity for muscarinic or noradrenergic (preceptors; unlike aripiprazole, it has virtually no affinity for 5-НТ2А and 5-НТ2с, noradrenergic α1, or histaminergic receptors. It remains unclear if these differences will cause significant variance between the efficacy of aripiprazole and bifeprunox. Researchers postulate that bifeprunox’s mechanism of action, which is similar to that of aripiprazole, will result in fewer motor side effects (e.g., extrapyramidal symptoms) and better efficacy against negative and cognitive symptoms than currently available serotonin-dopamine antagonists in addition to possibly providing some antidepressant and anxiolytic effects. Aripiprazole has not been able to fulfill these claims, and it is unlikely that bifeprunox will be able to given that its mechanism of action is so similar.
The developer’s announcements of clinical data suggest that bifeprunox has good efficacy with limited side effects. According to a Solvay press release dated September 2, 2003, a Phase II placebo-controlled study found bifeprunox efficacious and well tolerated, with little propensity to cause weight gain, extrapyramidal symptoms, or cardiovascular side effects. In an open-label Phase I study involving six healthy males, no clinically relevant changes were seen in laboratory, electrocardiogram, or vital sign parameters. In this Phase I study, the elimination half-life of the drug was nine hours, with preservation of high receptor occupancy at 24 hours, indicating that bifeprunox may be amenable to once-daily dosing.
Preclinical data suggest the drug could relieve negative and cognitive symptoms as well as depression and anxiety. In preclinical models, bifeprunox demonstrated a combination of antipsychotic, antidepressant, and anxiolytic properties. For example, it suppressed apomorphine-induced climbing in mice, inhibited conditioned avoidance-response in rats, and suppressed ultrasonic vocalization in rats placed in a threatening milieu. Primates treated with the drug exhibited increasing reactivity and alertness to environmental stimuli, suggesting that the drug may improve the negative and cognitive symptoms of schizophrenia.
Developed by A. Carlsson Research, ACR-16 is a dopamine stabilizer. In November 2002, the compound was in Phase lb trials for the treatment of schizophrenia. In March 2003, Merck licensed development and marketing rights to compounds from Carlsson’s dopamine stabilizer program, of which ACR-16 is the lead agent.
Similar to aripiprazole and bifeprunox, ACR-16 works as a dopamine antagonist and agonist. Given that only limited data have been released regarding its specific mechanism of action, it is assumed here that it works in a manner similar to that of other dopamine partial agonists. No clinical or preclinical data have been published on this compound, but it is expected to have efficacy and tolerability similar to that of aripiprazole and bifeprunox.
Glycine NMDA-Associated Agonists
Glutamate modulators that act as agonists at central N-methyl-d-aspartate receptors carry the promise of reducing negative symptoms to a greater degree than currently available therapies do. Two glycine N-methyl-d-aspartate-associated agonists are being evaluated: D-cycloserine and glycine. Because glycine is a nutritional supplement unlikely to gain regulatory approval, the discussion here focuses on D-cycloserine, a pharmaceutical that has a greater chance of obtaining formal approval.
Mechanism Of Action
Some researchers believe that schizophrenia is caused, at least in part, by a blockage or abnormality in the N-methyl-d-aspartate receptor. This theory is supported by the observation that the drug phencyclide, which can induce symptoms of schizophrenia in healthy people, acts by blocking the N-methyl-d-aspartate receptor. Furthermore, researchers have found increased levels of a naturally occurring N-methyl-d-aspartate-blocking agent, N-acetylaspartylglutamate (NAAG), in the postmortem brains of patients with schizophrenia. Researchers speculate that if schizophrenia is due to a blockage in the N-methyl-d-aspartate receptors, the disease could be reversed by reversing this blockage by activating the N-methyl-d-aspartate receptor. Because of their neuro-toxic and convulsive potential, direct, nonspecific N-methyl-d-aspartate-receptor agonists cannot be used. Therefore, researchers have focused on developing subtype-selective compounds to modulate N-methyl-d-aspartate-receptor function. Glycine N-methyl-d-aspartate-associated agonists appear to act by opening the glycine-binding site on the N-methyl-d-aspartate receptor, thus priming the N-methyl-d-aspartate receptor to respond in the presence of glutamate.
Originally, Searle (now Pfizer) was conducting Phase II trials with D-cycloserine, a partial glycine N-methyl-d-aspartate-associated agonist, for the treatment of Alzheimer’s disease. In 1995, the company discontinued the trials because D-cycloserine did not significantly improve cognition. Since then, researchers from various nonindustrial sources have been investigating the potential utility of D-cycloserine in patients with schizophrenia. Currently, the National Institutes of Mental Heath is conducting a Phase III trial to compare the effects of D-cycloserine and glycine (unlike D-cycloserine, glycine is a full glycine N-methyl-d-aspartate-associated agonist, an attribute that may allow it to be prescribed with clozapine) for treating negative symptoms in patients with schizophrenia. This placebo-controlled trial planned to enroll 45 patients with schizophrenia who will be randomized to receive D-cycloserine plus clozapine, glycine plus clozapine, or placebo plus clozapine for eight weeks. Cycloserine (Elan/Eli Lilly’s Seromycin) is currently marketed for the treatment of tuberculosis.
Clinical trials with D-cycloserine demonstrated that the drug can moderately reduce negative symptoms when administered in a narrow dose range (i.e., 50-100 mg) and concomitantly with an antipsychotic. For example, in a double-blind, placebo-controlled, six-week trial, 24 inpatients with treatment-resistant schizophrenia were randomized to add either D-cycloserine (50 mg) or placebo to their fixed dose of antipsychotic medication. Patients were assessed biweekly with the Positive and Negative Syndrome Scale, Hamilton Depression Rating Scale, Simpson-Angus Rating Scale, and Abnormal Involuntary Movement Scale. Half of the patients who completed the study were receiving either risperidone or olanzapine. The other half were receiving typical antipsychotics. At the study end, treatment with D-cyloserine led to a 15.2% reduction in Positive and Negative Syndrome Scale negative symptoms score, a 10% reduction in Positive and Negative Syndrome Scale general psychopathology score, and a 10.6% reduction in Positive and Negative Syndrome Scale total score. These scores at the study end were significantly reduced compared with baseline. The type of antipsychotics (atypical versus typical) did not appear to influence the efficacy of D-cycloserine. Scores on the other tests did not drop significantly with D-cycloserine treatment. No symptoms improved significantly with placebo treatment. D-cycloserine was well tolerated and not associated with changes in serum chemistry or hematological values.
Interestingly, D-cycloserine appears to increase negative symptoms when dosed concomitantly with clozapine, even though it reduces these symptoms when dosed with other antipsychotics. Seventeen outpatients diagnosed with schizophrenia who were treated with clozapine were randomized to receive six weeks of D-cycloserine (50 mg) or placebo in a crossover design separated by a one-week placebo washout. Eleven patients completed the 13-week study. D-cycloserine significantly worsened ratings of negative symptoms compared with placebo but did not significantly affect ratings of psychotic symptoms. Researchers theorize that the differing effects of D-cycloserine on negative symptoms when added to clozapine compared with conventional antipsychotics suggest that activation of the glycine recognition site may play a role in clozapine’s efficacy for negative symptoms. (Clozapine is more effective than typical antipsychotics for negative symptoms of schizophrenia.) The researchers speculate that D-cycloserine, which is a partial agonist, may act as an antagonist at the glycine site in the presence of clozapine.
Nicotinic Acetylcholine Agonists
Several pharmaceutical companies, including Pfizer, Abbott Laboratories, Taiho, Memory Pharmaceuticals, and Roche, are investigating nicotinic acetylcholine agonists in preclinical studies. The discussion here focuses on Abbott’s ABT-089 because it is the only drug in this class that has reached clinical development (although it has been suspended).
Mechanism Of Action
The activation of nicotinic acetylcholine receptors enhances the release of several neurotransmitters involved in focus, attention, executive function, learning, and memory. Deficits in nicotinic acetylcholine receptors have been reported in schizophrenia, and researchers postulate these deficits may contribute to the cognitive dysfunction (especially attention) seen in schizophrenia. Furthermore, the nicotinic acetylcholine receptors (specifically the a 7 nicotinic acetylcholine receptors) may participate directly in the pathophysiology of schizophrenia. Evidence supporting genetic linkage to schizophrenia has been reported on chromosome 15 in the region of the a 7 nicotinic acetylcholine receptor.
Abbott Laboratories is developing the nicotinic acetylcholine agonist ABT-089, which entered U.Spain. Phase II trials in May 2003. However, according to the company, although the drug is still considered “active,” it is on “clinical hold.” ABT-089 is considered a potential treatment for the cognitive dysfunction associated with schizophrenia. It is also being evaluated for the treatment of cognitive defects seen in Alzheimer’s disease and attention-deficit/hyperactivity disorder.
In preclinical studies, ABT-089 demonstrated cognition-enhancing effects and appeared to have good oral bioavailability and neuroprotective properties against glutamate-induced toxicity. During the company’s R&D update on May 29, 2003, Abbott stated there were signs of efficacy in the Phase I trial and that treatment was well tolerated, but the company did not release the full results.
If approved, ABT-089 will be dosed concomitantly with an antipsychotic. The compound has the potential to be a once-a-day formulation, which bodes well for the drug given that it will be dosed in a regimen.