Diagnosis and Management Considerations in Acute and Maintenance Treatment of Schizophrenia

Diagnosis and Etiology

Dr. Harvey is Professor of Psychiatry, Mount Sinai School of Medicine

Schizophrenia as an illness concept has been controversial since its first definitions in the late 1800s. For example, Kraepelin defined dementia praecox as an illness entity with an early onset, a deteriorating course with dementia-like symptoms, and profound cognitive and functional impairments. Bleuler disagreed about the issues of onset age and invariably poor outcome, but agreed on the centrality of cognitive, functional, and emotional changes in the illness.

As in all DSM diagnoses, the criteria for schizophrenia are multidimensional, including the presence of active illness, a specified duration of symptoms, and exclusions of alternative causes of the symptoms. The symptoms used to define schizophrenia are the same as those noted by Kraepelin and Bleuler and, interestingly, the controversies are still the same as well.

Important Features of Current Criteria

The most important feature of the current criteria is the specification of active illness, which includes the presence of at least two symptoms of illness (Table 1), unless either the delusions or hallucinations are “characteristic” in nature. In that case a single symptom satisfies the active illness criteria. Characteristic delusions are those that are completely impossible and are designated as “bizarre.” These include delusions of being controlled, of having thoughts either inserted or removed, or monitored in ways that are impossible, such as with two-communication from the television. Characteristic hallucinations are those that involve hearing voices spoken directly to the subject, hearing voices commenting on the subject’s thoughts, actions, or appearance, or hearing two or more voices conversing with each other.

Another important feature of the current criteria is that deterioration in functioning from previous levels of at least 6 months is required in order to substantiate the diagnosis.

One of the most important aspects of schizophrenia is the presence of substantial functional disability. The majority of patients have deficits in social functioning, the ability to live independently, and the ability to obtain and sustain employment. This disability leads to substantial indirect cost of the illness, because many individuals with schizophrenia never develop the adaptive skills that are required to succeed in independent life.

A primary determinant of functional disability is impairment in cognitive functions.¹ While most of the classical cognitive ability domains are impaired in schizophrenia, including attention, memory, problem solving, and language skills, the greatest relative deficits appear to be in episodic memory (the ability to learn information with exposure and practice and to recall it after a delay) and, to a lesser extent, attention and working memory (the ability to maintain and manipulate information in short term storage) skills. As noted above, these impairments in cognitive functioning have been noted since the earliest definitions of the illness over 100 years ago.

Common Comorbidities

Common comorbidities in schizophrenia include substance abuse and obesity (Table 2). While obesity may be partially treatment related, the typical social class of people with schizophrenia leads to a poor diet and nutritional problems. Smoking is very common in schizophrenia and this may be influenced by genetically transmitted deficiencies in receptors for the nicotinic cholinergic receptor system.

Course of Illness

The course of schizophrenia is marked by several different phases of illness. These include the premorbid period, a prodromal period where normal functioning is altered, and the psychotic phase. After the first episode of psychosis, recovery is usually incomplete and relapse is very common (Figure 1).

At the time of the first episode, the signature of both clinical symptoms and cognitive impairments is consistent with that seen in more chronic patients.² See Figure 2 for a comparison of the level of impairments in treatment naïve and previously treated patients. While a good treatment response of the diagnostic symptoms of the illness is seen in as many as 90% of patients, this response is often disproportionately greater than the rate of functional recovery. As many as 50% of people with schizophrenia are experiencing a disability within 6 months of their first treatment and as many as 95% of patients relapse within 5 years. Full functional recovery is quite rare and fewer than 20% of patients have both sustained remission of their symptoms and achievement of success in vocational and social functioning.³

Genetic Factors

Etiological factors have proven complex to identify. Genetics are clearly involved, as the familial risk rates are much higher than the general population and susceptibility genes have recently been identified (Table 3). However, the risk rate for schizophrenia is much less within family members than would be predicted with strictly Mendelian patterns of heritability. For instance, if both parents have schizophrenia the risk is about 40%, similar to having a monozygotic twin with the illness and the risk for children and siblings of people with schizophrenia appears to be about 10% to 15%. Therefore, there is reason to suspect that a combination of pre- and perinatal stress, combined with genetic risk, confers maximum vulnerability to the development of the illness. In terms of specific susceptibility genes, there is evidence for familial alterations in the functioning of the genes that are related to receptor sensitivity and density for the cortical a-7 nicotinic receptor. Further, there is evidence substantial down regulation of genes that are responsible for maintenance of white matter integrity.

Neurodegeneration and Deterioration

The general course of schizophrenia shows some evidence of deterioration. Patients show evidence of modest but consistent enlargement of their cortical ventricles and reduced latency to clinical response following successive exacerbations.³ While there is limited evidence suggestive of cognitive or functional decline over the middle of the lifespan, the evidence of consistent ventricular enlargement, found across samples with large variation in age and clinical status at the time of the first assessment, suggests that there are progressive neurobiological processes active across the lifespan course of the illness.

Finally, while postmortem specimens that would suggest that typical neurodegenerative influences are no more common than in the general population, there is some evidence of neurodegeneration. Cellular architecture appears altered and the density of certain cortical layers in reduced. The arrangement of white matter appears altered as well, with these tracts less well “bundled” than in healthy individuals.