Understanding Schizophrenia: Recent Advances in Etiology and Changing Models of Treatment

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The Glutamate Hypothesis. Glutamate (GLU) is the primary excitatory neurotransmitter in the brain. GLU is critical for neuron migration and survival in early development, neuronal plasticity in adolescence, and for neuronal excitability in adulthood. GLU is implicated in schizophrenia, a disease in which abnormal neuronal development, neuronal regulation, and neurotoxicity may play a role in pathophysiology.

The glutamate hypothesis arose from observations of similarities between schizophrenia and psychosis caused by phencyclidine (PCP), an antagonist of glutamatergic receptor N-methyl-D-aspartate (NMDA) (Bernstein, 2008). PCP and other NMDA receptor antagonists could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects (Coyle, 2006).

The NMDA receptor hypofunction hypothesis suggests that NMDA receptors attached to GABA interneurons that communicate between primary and secondary GLU cortical neurons are underactive. These NMDA receptors make the GABA interneuron less often, firing less often. This loss of GABA output to the secondary GLU neuron causes it to fire more often, directly causing the firing of excessive DA in the mesolimbic pathway, triggering psychotic symptoms (Schwartz et al., 2012). This NMDA receptor hypofunction hypothesis gained additional support from the finding that ketamine, also an NMDA receptor antagonist, exacerbates psychotic symptoms in schizophrenics but not in individuals who have no mental illness (Castle & Buckley, 2015). Additional support came from the finding that antipsychotics that enhance NMDA receptor function significantly reduced negative symptoms and improved cognition in patients with schizophrenia (Coyle, 2012). Additionally, persistent blocking of NMDA receptors triggers schizophrenic symptoms in animals, including downregulation of cortical GABAergic neurons and defective development of pyramidal neuron dendrites. Abnormalities in GABA and pyramidal neurons have been described in schizophrenic brains (Costa et al., 2001).

Diagnosing Schizophrenia

The diagnosis of schizophrenia is based on clinical presentation of symptoms and history according to diagnostic criteria outlined in the DSM-V. Individual symptoms that have been found to be highly predictive of schizophrenia, called Schneider’s ‘first-rank’ symptoms, aid diagnosis. The physician may also look for more frequent symptoms (such as prominent hallucinations or inappropriate social behavior). A minimum duration of 6 months in DSM-V is indicated. Diagnosis of schizophrenia cannot co-occur with (i) organic mental disorder, (ii) major depression (iii) mania, or (iv) autistic disorder (Castle & Buckley, 2015).

Treatment

Antipsychotic drug therapy is the hallmark of treatment. Most antipsychotic drugs aim to alleviate psychotic symptoms (hallucinations and delusions). Currently, there are two forms of antipsychotics: the older ‘typicals’ and the newer ‘atypicals’. There is no compelling evidence that newer atypical agents are more effective at treating the psychotic symptoms associated with schizophrenia (Bernstein, 2008). However, atypical antipsychotics (ie. clozapine) have lower risk of extrapyramidal side effects that complicate treatment by typical antipsychotics. Clozapine remains the most effective of the antipsychotics for patients who do not respond well do other medications, although risk of lethal side effects have been documented. Continuation of therapy reduces the risk of relapse. However, in 15 percent of subjects, long-term drug therapy (4 years or more) may risk the patient in developing tardive dyskinesia. The clinician should therefore weigh whether the benefits of continuing drug therapy outweigh the risks.

A comprehensive and longitudinal approach is necessary for effective treatment of schizophrenia. The recovery paradigm that has been strongly adopted in recent years places the individual at the center of their care. It aims to support patients in achieving their life goals in a holistic framework. The emphasis is not only on symptom relief, but also more broadly on well-being, social integration, and occupation. Patients actively participate in monitoring outcomes, conducting ongoing risk assessment, and assessing what relapse triggers.

Assertive community treatment is a model for assisting schizophrenic patients in community-type establishments. Often referred to as the ‘revolving door’ patients, individuals benefit from a high level of face-to-face contact (at least twice a week, 24hr/7-day cover optimum), the continued duration of long-term care, multidisciplinary team, and assertive follow up. This community-based care reflects a shift in the 1960s and 1970s disfavoring old ‘asylums’ and acute inpatient care. However, the rise of schizophrenic homeless in urban cities and high rate of noncompliance has drawn criticisms of community treatment (Castle & Buckley, 2015).

Current models of treatment offer acute inpatient care as short-term management of people in crisis, who have suffered relapse of illness and/or who cannot be safely managed in the community. The benefits of acute inpatient care include: group-based therapies, vocational training, safe environment, management of psychiatry symptoms with psychopharmacology, and psychoeducation.

Psychological treatment, particularly cognitive behavior therapy (CBT) has potential for helping people with ‘medication-resistant’ delusions, for vocational training, and for acceptance-commitment therapy.

Conclusion

Schizophrenia remains a widely misunderstood mental illness. In the clinical setting, common misconceptions hold that schizophrenia is characterized by a split or multiple personality or that it means holding two contradictory opinions simultaneously. Another inaccurate belief is that the mental state of schizophrenia is one of heightened creativity and originality. Recent shifts in understanding of the disease since the 2000s have redefined treatment. The 1960s saw a pendulum swing toward the deinstitutionalization of mentally ill patients toward community care. The current conditions of acute inpatient settings manage short-term crises and function to contain individuals who place a risk on themselves and others in society. In the 2000s, the recognition that community care remains ineffective (as evident by the homeless schizophrenic population) has lead to the recognition of the benefits acute inpatient care may provide. The etiology and pathology of schizophrenia remain unclear, although there is a strong evidence for genetic and environmental factors that predispose individuals to disease.