Balancing Therapeutic Safety and Efficacy to Improve Clinical and Economic Outcomes in Schizophrenia: A Clinical Overview
Published Online: June 27, 2014
Daniel C. Javitt, MD, PhD
Schizophrenia is a chronic and disabling psychiatric disorder that commonly presents during late adolescence and early adulthood.1 Although its prevalence is estimated to be up to 1% of the population worldwide, schizophrenia has profound effects on patients and their families due to the tremendous personal, social, and economic burdens it imposes on these individuals.2,3 Patients with schizophrenia have a greater likelihood of unemployment and homelessness, and the total economic burden of schizophrenia in the United States is estimated to be approximately $65 billion.1,3 Much research has been done on schizophrenia, but its exact etiology has yet to be determined and is likely multifactorial.
The onset of schizophrenia symptoms typically occurs between the late teens and the mid-30s. Patients with disease onset before age 17 years are considered to have early-onset schizophrenia (EOS), and those with onset before age 13 years are considered to have very early–onset schizophrenia (VEOS).4 The estimated prevalence of VEOS is 1 per 10,000 individuals, and the lifetime prevalence of developing schizophrenia is approximately 0.3% to 0.7%.4,5 Male patients tend to have an earlier onset of symptoms, between the ages of 15 and 25 years, whereas female patients have later onset, around age 19 to age 35 years. Further, male patients exhibit a higher lifetime risk of developing schizophrenia, with a male-to-female relative risk of about 1.4, and male patients often experience a more severe disease course.4,6
The exact cause of schizophrenia has yet to be determined, but it is likely heterogeneous and multifactorial.7 Although most patients with schizophrenia have no family history of psychoses, research in families of patients with schizophrenia has shown that there is likely a genetic component, and the risk of schizophrenia increases as the degree of genetic affinity with the patient increases. For example, if 1 individual in a pair of twins has schizophrenia, the risk of schizophrenia developing in the other twin is 10% to 15% for dizygotic twins, and increases to 40% to 50% in monozygotic twins.7 Despite the significant familial risk, however, no genes of large effect have been identified. This pattern could reflect either the epistatic interaction among multiple genes or the contribution of de novo mutations that arise and persist for only 1 or a few generations.8,9 Rare copy number variants converge, particularly on genes that affect glutamatergic synaptic networks and N-methyl-Daspartate (NMDA) receptors. Specific genes of interest include NRG1 (neuroregulin 1), DTNBP1 (dysbindin), DRD1-4 (dopamine receptors D1-D4), DISC (disrupted in schizophrenia 1), COMT (catechol-0-methyl-transferase), D-amino acid oxidase (DAAO), D-amino acid oxidase activator (DAOA), and GRM3 (metabotropic glutamate receptor). Despite advances in genetic studies, no particular gene variant has been shown to be sufficient to cause schizophrenia.7,10
In epidemiological studies, environmental factors such as urban settings, areas with high rates of migrants, exposure to cannabis during adolescence, and lower socioeconomic class have been linked to the development of schizophrenia. Maternal stress and/or infection (eg, influenza) during pregnancy, nutritional deficiency during the prenatal period, obstetric and perinatal complications (eg, fetal hypoxia), birth during late winter or early spring, and childhood trauma(s) can also increase the risk of development of schizophrenia.4,7,11 Older paternal age (>45 years) at the time of conception has also been associated with a more than 2-fold increased risk of the offspring developing schizophrenia.12,13
Magnetic resonance imaging studies of the brains of patients with schizophrenia have shown reductions in whole brain volume and grey matter volume, and the enlargement of ventricles. Reductions are also seen in temporal lobe areas, such as the hippocampus, amygdala, superior temporal gyri, prefrontal cortex, thalamus, anterior cingulate, and corpus callosum. It has been suggested that disturbances in the development of cerebral asymmetry can contribute to the etiopathogenesis of schizophrenia.14 Leftward asymmetry of the brain structure may also be reduced in patients with schizophrenia due to a larger right planum temporale compared with normal controls.14,15 Compared with adults with schizophrenia, patients with EOS appear to have similar brain structural changes, but more severe neuroanatomical alterations.14,16 The integrity of white matter connections between regions of the brain may also be compromised and lead to impairments, as revealed by diffusion tensor imaging, in such processes as behavioral regulation.17
Dopaminergic dysfunction has long been cited as the main cause of schizophrenia symptoms. It has been proposed that patients with schizophrenia have hypoactive mesocortical dopaminergic systems, which are responsible for negative and cognitive symptoms, and hyperactive mesolimbic dopamine systems, which are responsible for the positive symptoms.14,18 Presynaptic dopamine synthesis and release mechanisms may be most affected; however, dopamine abnormality does not explain all of the symptoms associated with schizophrenia.11,19 Current antipsychotic medications are effective for many individuals, but nevertheless, a high percentage of patients have no or only partial relief of symptoms, even with the best available agents. Persistent negative and cognitive symptoms are particularly associated with poor outcomes, and do not respond well to existing medications.11,20
There is increasing evidence that glutamatergic dysfunction is another possible cause of schizophrenia. The observation that NMDA receptor antagonists, such as phencyclidine and ketamine, can cause clinical symptoms similar to those seen in patients with schizophrenia suggests that schizophrenia may be related to a decrease in NMDA receptor function in the brain.21-23 More recently, NMDA receptor theories have been supported by the observation that antibodies to NMDA receptors may induce a psychotic state that resembles schizophrenia.24 As opposed to the dopamine system, which projects preferentially to basal ganglia and frontotemporal regions, the glutamate system is widely distributed throughout the brain and affects sensory regions, as well as those involved in such higher-order processes as memory or executive processing.23
Clinical Presentation and Diagnosis
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), released in May 2013, provides updated criteria for the diagnosis and classification of various mental disorders, including schizophrenia. For a patient to be appropriately diagnosed with schizophrenia, they should exhibit at least 2 Criterion A symptoms for a significant portion of time, defined as a 1-month period or longer, unless successfully treated before this 1-month period has elapsed. Criterion A symptoms include delusions, hallucinations, disorganized speech (eg, frequent derailment or incoherence), grossly disorganized or catatonic behavior, and negative symptoms (ie, diminished emotional expression or avolition). Patients should also show a reduced level of functioning in areas such as self-care, work, and interpersonal relations. Further, some signs of the disturbance, such as mumbling in public, magical thinking, or becoming more withdrawn, must persist for a continuous period of at least 6 months. Differential diagnoses, such as schizoaffective disorder, depressive or bipolar disorder with psychotic features, and psychosis caused by a substance or medical condition should be ruled out.25
Compared with DSM-IV, in which only 1 Criterion A symptom is required for diagnosis of schizophrenia if the delusions are bizarre (ie, clearly implausible and inconsistent within the culture or from ordinary life experiences) or if hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts or consist of 2 or more voices conversing with each other, DSM-5 requires patients to have 2 or more Criterion A symptoms regardless of the characteristics of the delusions or hallucinations. Other communication disorder of childhood onset was added to Criterion F. Additionally, DSM-5 does not distinguish the subtypes of schizophrenia, such as paranoid, disorganized, catatonic, undifferentiated, and residual, due to the lack of clinical utility and diagnostic value.26
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