Pharmacotherapeutic Approaches in the Treatment of Schizophrenia

Schizophrenia is a mental illness characterized by disruptions in cognition, affect and behaviour (WHO 1993). The disease was conceptualized more than a century ago as dementia praecox, one of the two categories of psychoses delineated by Kraepelin and differentiated from manic depression, the other category, due to symptoms such as abnormalities in cognition and emotion that have subsequently been designated as negative symptoms (Andreasen 2011, p. 1907). Despite the early identification, an absolute cure for schizophrenia does not exist with available treatments, which target various neurotransmitter receptors, being partially effective (Collier & Li 2003). This paper highlights the pharmacotherapeutic approaches for treating schizophrenia and discusses new treatment approaches. First, however, a brief background on the epidemiology, pathology, pathophysiology and potential causes of schizophrenia is presented.

Background to the Disease

Epidemiology (Prevalence and Incidence) of Schizophrenia

Estimates of prevalence of schizophrenia per 1000 individuals vary between 0.3 to 11 (Hafner & Heinden 1997, p. 141; Saha et al. 2005, p. 0428). In Australia, the Schizophrenia Research Institute (SRI) estimates the lifetime prevalence at 1 % i.e. 10 per 1000 individuals (2010). Higher prevalence has been observed in males than females, in urban-born than rural-born populations and in migrant than non-migrant groups (McGrath et al. 2004; Aleman, Kahn & Selten 2003). In respect to incidence rates, McGrath et al. (2004) reports the median incidence rate of schizophrenia to be 15.2 per 100,000 persons. An early observation cited by Hafner and Heinden (1997, p.143) places Australian incidence rate at 18 persons per 100,000 individuals, while SRI estimates the annual incidence rates to be 2000 persons (2010).

Symptoms/pathology

The diagnosis criteria for schizophrenia stipulated by ICD-10 and DSM-IV highlight various symptoms of the disease. ICD-10 is the tenth edition of the medical classification list maintained by the World Health Organization that highlights diagnosis criteria and symptoms of various diseases (WHO 1993). DSM-IV is the fourth edition of a diagnostic and statistical manual published by the American Psychiatric Association (APA) that classifies mental disorders (APA 2012). Positive symptoms of schizophrenia include delusional perceptions, hallucinatory voices, incoherent or irrelevant speech, and audible thoughts (WHO 1993; van Os & Kapur 2009; Arango & Carpenter 2011, p. 1916). Schizophrenia-induced delusions vary widely in content, with the most common form being delusional persecution, which is exemplified by a scenario where the patient believes that undesired people are following him wherever he goes (Arango & Carpenter 2011, p. 1916).

Negative symptoms are the things that patients do not do i.e. omissions rather than commission of particular behaviour. The negative symptoms include incongruity or flattening of emotional responses (patients do not express expected emotions), alogia (poor speech or poor content of speech), and anhedonia (patients are unable to experience pleasure) (WHO 1993; Breier 1995; van Os & Kapur 2009; Arango & Carpenter 2011, p. 1916). Other negative symptoms are apathy (patients exhibit a general lack of interest), asociality (patients lack interest in social contacts) and avolition – lack of motivation (WHO 1993; Breier 1995; van Os & Kapur 2009; Arango & Carpenter 2011, p. 1916).

Pathophysiology

Neuroimaging assays highlight that schizophrenics’ brains have subtle decreases in grey matter, focal alteration of white matter and an enlargement of ventricles (van Os & Kapur 2009). Such assays also indicate an elevated density of dopamine receptors in the basal ganglia of schizophrenics (Farde 1997), a factor that results into increased dopamine transmission in diverse regions of the brain (van Os & Kapur 2009). The link between increased dopamine transmission and experiences reported by schizophrenics has been the subject of recent theories. One candidate theory explains such experiences to result from aberrant firing of the dopamine system. The aberrant firing results in aberrant attachment of motivational salience to actions, objects and people with the schizophrenic interpreting such aberrant experiences as delusional perceptions (van Os & Kapur 2009; Murray, Lappin & Di Forti 2008).

Causes of schizophrenia

Although the specific exposures that result into schizophrenia remain unknown, evidence has implicated genetic and environmental factors. Genetic evidence arises from twin studies showing syndrome heritability rates of around 80% for schizophrenia (van Os & Kapur 2009; Tandon, Keshavan & Nasrallah 2008). Although the precise mechanism of inheritance remains unclear, it is thought that mutations in the X-chromosome, deletion of 22q11 and reciprocal translocation of 1q42/11q14 increases the risk of developing schizophrenia (Tandon, Keshavan & Nasrallah 2008). 22q11 deletion’s role in schizophrenia is unclear, but it is thought that one or more important gene(s) could lie within the deleted region (Sporn et al 2004). 1q42/11q14 translocation is argued to disrupt DSC1 and DSC2 genes; DSC1 encodes a multifactorial protein, DSC1, which functions in multiple protein-protein interactions (Hodgkinson et al. 2004). Such disruption is observed in many schizophrenics (Hodgkinson et al. 2004). Other genes of interest include DRD1-4 (encodes for dopamine D1-D4 receptors), NRG1 (encodes for neuroregulin 1), COMT (encodes for catechol-O-methly-transferase) and GRM3 (encodes for metabotropic glutamate receptor) (Tandon, Keshavan & Nasrallah 2008; Collier & Li 2003). Environmental factors are exemplified by higher incidence rates recorded for urban areas compared to rural areas and immigrants compared to non-migrant groups (van Os & Kapur 2009). Perinatal and early childhood environment such as parent malnutrition, maternal stress and maternal infection are also associated with a higher risk for a child developing schizophrenia (van Os & Kapur 2009; Tandon, Keshavan & Nasrallah 2008). Go to part 2 here.

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