OVERVIEW

Psychosis, in a broad sense, signifies impaired reality-testing ability. The most important symptoms of psychosis are delusions and hallucinations, although other signs and symptoms (such as disorganized speech or behavior and catatonia) are also considered psychotic phenomena.

Psychosis is not a specific diagnosis, because it can occur in a wide variety of clinical contexts. Of the psychotic disorders, the prototypical condition is schizophrenia. In schizophrenia, psychotic symptoms occur chronically, without gross organic abnormalities of the brain (hence the term functional psychosis) or a severe medical disturbance (as in a delirium). Moreover, psychosis may occur when the mood is normal, thus differentiating it from bipolar disorder or from psychotic depression. While psychosis is a defining (and often the most apparent) clinical feature of schizophrenia, other symptom clusters (e.g., negative symptoms and cognitive symptoms) are largely responsible for the psychosocial disability that usually accompanies this disorder.

Schizophrenia was originally described at the close of the nineteenth century by Emil Kraepelin (who categorized madness into episodic mood disorders and chronic psychotic illnesses; he termed the latter dementia praecox, which was later renamed schizophrenia by Eugen Bleuler). In the 100 years since the condition was identified, much progress has been made (in large part the result of the discovery of the first antipsychotic, chlorpromazine), turning schizophrenia from an illness treated in asylums (state hospitals) to one treated in community settings (Figure 28-1).¹ However, the fundamental Kraepelinian dichotomy between schizophrenia (and related psychotic disorders) and manic-depressive illness has remained unchanged.

Figure 28-1 Timeline of 100 years of schizophrenia in the United States.

(Source: Shorter E: A history of psychiatry: from the era of the asylum to the age of Prozac, New York, 1997, John Wiley & Sons; Geller JL: The last half-century of psychiatric services as reflected in psychiatric services, Psychiatr Serv 51:41-67, 2000.)

EPIDEMIOLOGY AND RISK FACTORS

Schizophrenia is a syndrome that occurs in all cultures and in all parts of the world. Epidemiological studies have found incidence rates between 7.7 and 43.0 (median 15.2) new cases per 100,000.² The point prevalence is approximately 5 per 1,000, and the lifetime morbidity risk is approximately 1%. Gender differences exist; males have a 30% to 40% higher lifetime risk for schizophrenia than females,³ and the age of onset is roughly 3 to 4 years later for females.⁴

The old dogma that cited the identical incidence and prevalence rates of schizophrenia around the globe is not quite correct. Clear geographical differences exist, albeit within a fairly narrow range of twofold to threefold differences. The fact that these modest variations in rates exist between cultures, and within subgroups in cultures, likely reflects different risk factors for schizophrenia in different populations.

The best-established risk factors are not genetic, but environmental (Table 28-1). Immigrant populations have an increased risk,⁵ with the highest risks for the children of first-generation immigrants, followed by the immigrants themselves.⁶ Urban living increases risk relative to rural living.⁷ Etiological insults during brain development include intrauterine infections, particularly influenza,⁸ and nutritional deficiencies. Maternal starvation has strong support from two epidemiological studies of famines (the Dutch Hunger winter of 1944-1945⁹ and the 1959-1961 Chinese famine¹⁰). Both studies found a doubling of risk for schizophrenia in offspring of mothers who starved during the first trimester. Other early environmental risk factors include obstetrical complications.¹¹ Later environmental risk factors are head injury¹² and substance use (particularly cannabis).¹³ Frequent pre-morbid cannabis use (i.e., more than 50 uses) increases the risk for the development of schizophrenia by sixfold.¹⁴

Table 28-1 Risk Factors for Schizophrenia

References: 6, 11, 12, 109.

The majority of patients with schizophrenia lack a family history of the disorder. Nevertheless, the fact that genes matter was shown in now-classic twin and adoption studies of the 1960s. For monozygotic twins, the risk of developing schizophrenia approaches 50% for the unaffected twin if the co-twin has schizophrenia. Having siblings or parents (i.e., first-degree relatives) with schizophrenia increases an individual’s risk to approximately tenfold above that seen in the general population. With greater genetic distance, the risk for schizophrenia decreases to a twofold risk over the population risk for second-degree relatives.¹⁵

Paternal age increases the risk for schizophrenia in a linear fashion. Compared with the children of fathers who are less than 25 years old, the relative risk for children increases steadily with paternal age, to about 2.0 for fathers in the 45 to 49 age-group, and to almost 3.0 for fathers older than age 50.¹⁶ This increase in risk with paternal age is consistent with the hypothesis that de novo mutations contribute to the genetic risk in schizophrenia. New mutations could explain why a disorder with lower fertility rates has not disappeared; in males as opposed to females, the germ-line cells, spermatogonia, continue to divide throughout life, allowing replication errors to accumulate and to be transmitted to offspring.

It is unlikely that a single gene with a significantly large effect will be found that can cause schizophrenia. Most likely, schizophrenia is similar to other non-Mendelian complex disorders where many different genes each make a small, yet important, contribution to disease vulnerability. Such vulnerability genes convey susceptibility without directly causing the disease: the disease is only expressed when combined with other genes or certain environmental factors (e.g., infection or drug use). The number of susceptibility genes is unknown; however, many genes can confer risk in a population. In recent years, several susceptibility genes have been tentatively linked to schizophrenia (for a list of strongest candidates, see Table 28-2).¹⁷ The most promising candidate genes are involved in brain development, frontal lobe function, myelination, synaptic function, and glutamate transmission. It is likely that most genes are not specific for schizophrenia; instead, they confer risk for neuropsychiatric disorders that cut across current clinical diagnoses. Several genetic disorders, such as 22q11 deletion syndrome (velo-cardio-facial syndrome [VCFS] or DiGeorge syndrome) or Klinefelter syndrome (XXY syndrome), increase the risk for psychosis in affected individuals.^18,19

Table 28-2 Candidate Genes for Schizophrenia

Gene selection based on reference 17.

An interaction between susceptibility genes and environment forms the basis for the neurodevelopmental hypothesis of schizophrenia in which a clinically silent, latent propensity toward schizophrenia (e.g., a genetic vulnerability or insult during brain development, such as intrauterine infections or maternal starvation) gets uncovered when the brain matures (e.g., during the naturally occurring pruning of dendritic arborization) or additional insults (e.g., cannabis use) push a vulnerable brain toward psychosis.²⁰ Since the clinical picture (phenotype) is not solely determined by the gene sequence (genotype), but rather by which genes are expressed (the epigenotype), some gene-environment interactions may occur via epigenetic modifications of the genome. Functionally, disconnection between frontal and hippocampal regions has been suggested to account for the emergence of clinical symptoms in this developmental model.

PATHOPHYSIOLOGY

Evidence from neurochemistry, cellular neuropathology, and neuroimaging studies supports the idea that schizophrenia is a brain disease, that is, a disease manifest by abnormalities in brain structure, brain function, or both. The observed abnormalities are thus far of limited specificity and sensitivity, and have therefore not yet had clinical relevance for diagnosis and treatment, and only limited value in prognostication. Furthermore, there is no single universally accepted theory regarding the brain dysfunction seen in schizophrenia, but rather there are a host of competing and overlapping models. (For an example of a model of auditory hallucinations that combines neuroanatomical and neuroimaging findings, see Figure 28-2.)

Figure 28-2 The neural basis for auditory hallucinations. Schematic showing selected evidence from the literature regarding the role of the prefrontal and superior temporal cortices, and their interconnections, in the development of auditory hallucinations.

Changes in Brain Structure

From the very first images of the human brain, first indirectly by the now-outdated pneumoencephalography, later directly by using computed tomography (CT), one major finding emerged: patients with schizophrenia had larger ventricular volumes than did matched sets of non–mentally ill controls.³³ The impact of this finding, which has subsequently been replicated many times using magnetic resonance imaging (MRI), cannot be overstated, because for the first time there was visual evidence of schizophrenia as a brain disease (Figure 28-3). There were (and are) two major limitations to this much-replicated finding: first, ventricular enlargement is neither specific nor sensitive enough to use as a diagnostic tool; second, ventricular enlargement is neuroanatomically vague, making it nearly impossible to link this change with the psychotic phenomena seen clinically.

Figure 28-3 MRI of enlarged ventricle in schizophrenia. Example of ventriculomegaly in a patient with schizophre-nia. High-resolution magnetic resonance images from a 42-year-old man without mental illness (left) and a 46-year-old man diagnosed with schizophrenia (right). Note the expanded volume of both the body (long arrow) and temporal horn (short arrow) of the lateral ventricle, the latter finding suggestive of hippocampal atrophy.

Subsequent work has attempted to find structural differences within the cerebral cortex and the subcortical nuclei. Although structural differences have been observed in a number of areas across the cortical mantle,^34,35 the hippocampus stands out as a region where there have been well-replicated findings. Meta-analyses of classical volumetric analyses of imaging data indicate that on average, hippocampal volumes are 4% smaller in patients with schizophrenia than in matched controls.³⁶ Similar volumetric changes within the medial temporal lobe have been confirmed from a meta-analysis of studies using the newer voxel-based morphometric approach.³⁷ Some of the volume changes might occur concurrent with the development of psychosis.³⁸ Using diffusion tensor imaging (DTI), it can be shown that the integrity of white matter tracts is compromised in schizophrenia, consistent with disconnectivity between brain regions.³⁹

CLINICAL FEATURES AND DIAGNOSIS

The diagnosis of schizophrenia is made clinically, based on a typical combination of symptoms (present cross-sectionally and longitudinally), in the absence of other psychiatric or medical conditions that would explain the symptoms (see below). The exact number and combination of symptoms, as well as the required duration of symptoms to make a diagnosis of schizophrenia, differ depending on the classification system used (Table 28-3). Making a diagnosis based on clinical symptomatology and course alone, without the help of genetic markers or biomarkers, can lead to different diagnoses over time (even in the same patient if the clinical picture changes).

Table 28-3 Key Diagnostic Features in Schizophrenia in DSM-IV and ICD-10

Based on references 117 and 118.

* These hallucinatory-paranoid symptoms are based on Schneiderian first-rank symptoms.

Schizophrenia is a disorder with an onset in late adolescence or early adulthood. Most patients (80%) present with schizophrenia between 15 and 45 years of age. Onset during childhood or in late life is possible, but not common. Onset at the extremes of the age range show continuity with typical-onset schizophrenia, although the onset of psychosis after age 50 should raise suspicion for a secondary psychosis.

The onset of schizophrenia can be acute (i.e., symptoms develop over a few days) or subacute (i.e., symptoms develop over a month), although a more insidious onset with signs of the illness beginning many months or even years before frank psychosis is usually seen (Figure 28-4). A nonspecific prodromal phase can often be ascertained retrospectively. Pro-dromal symptoms include attenuated psychotic symptoms (e.g., suspiciousness, perceptual distortions, or perplexity), depression and suicidality, obsessive thinking, and sleep problems. Role failure and loss of social competence are typical features.⁴⁵ However, the progression to schizophrenia for patients in a putative prodromal state is not inevitable, with one study reporting a 1-year conversion rate of 41%.⁴⁶ Unfortunately, even after the development of clear-cut psychosis, the patient and his or her family and friends often do not recognize it. Even when recognized, the affected individual often resists treatment. This results in untreated psychosis that lasts on average almost 2 years.⁴⁷ The duration of untreated illness, which includes the prodromal period and the duration of untreated psychosis (DUP), can last several years, and typically results in disrupted psychological and social development and impaired role function. The prodromal period is an area of active research, since the functional impairment in cognitive decline seen in schizophrenia occurs before the onset of psychosis and remains stable even after recovery from psychosis.⁴⁸ Exactly when the cognitive decline begins remains uncertain, but early signs of the disturbance (as judged by scholastic records) point toward onset in middle school or even earlier, possibly with further worsening around the time of psychosis.⁴⁹

Figure 28-4 Typical time course of symptoms in a first episode of schizophrenia. (Patient with insidious onset over several years. If onset is acute or subacute without premorbid deficit, the residual symptoms are less pronounced or nonexistent.)

Table is based on references 119–122.

The hallmarks of acute schizophrenia are hallucinations and delusions, sometimes grouped together as positive symptoms. Hallucinations are perceptions without an external stimulus, and they can occur in any sensory modality (Table 28-4). However, by far the most common type of hallucination is auditory, occurring in at least two-thirds of patients over the course of their illness. Certain types of third-person (Schneiderian) hallucinations are frequently encountered: several voices talking about the patient, often in a derogatory way; a voice giving a running commentary on what the patient is doing; or a voice repeating what the patient is thinking. While hallucinations in other modalities are possible, visual or olfactory hallucinations in particular should raise the suspicion for an organic etiology of the hallucinations.

Table 28-4 Types of Hallucinations by Modality in Schizophrenia and Other Conditions

Delusions are false, nonculturally sanctioned beliefs that are held with great conviction, even in the face of overwhelming evidence to the contrary. Table 28-5 outlines common delusional themes. The delusional idea puts the patient at odds with his or her culture or subculture. The content of delusions can be nonbizarre (feasible) or bizarre (impossible based on the laws of physics). By convention, bizarre delusions suggest schizophrenia and exclude delusional disorder.

Table 28-5 Types of Delusions by Content in Schizophrenia and Other Conditions

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Tags: Massachusetts General Hospital Comprehensive Clinical Psychiatry

Jun 8, 2016 | Posted by admin in PSYCHIATRY | Comments Off on 28: Psychosis and Schizophrenia

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Persecutory

A person or force is interfering with the patient, observing the patient, and wishing to harm the patient (e.g., poisoning him or her). These can be family members, co-workers, government agencies (e.g., the CIA or FBI), or even aliens or the devil. Very common theme in delusional disorder or schizophrenia.

Reference

Random and innocuous events (e.g., a news item in the morning newspaper, an incidental comment or gesture by a stranger) take on personal significance and meaning.

Control