Psychosis

Jacob S. Ballon

T. Scott Stroup

INTRODUCTION

Psychosis is characterized as a detachment from reality, often including hallucinations or delusions. Psychotic symptoms are a core feature of schizophrenia but may also be seen in other serious psychiatric disorders including bipolar disorder, major depressive disorder, and posttraumatic stress disorder (PTSD). Importantly, psychosis may also be a prominent symptom in many neurologic disorders, other medical conditions, substance intoxications, and withdrawal syndromes. New-onset psychosis should prompt a thorough workup to determine the etiology of such symptoms.

Psychotic experiences can be characterized as phenomena in which sensory experiences are generated by aberrant brain stimuli rather than external inputs. Hallucinations can be auditory (e.g., hearing voices), visual (seeing objects that are not there), or can occur in other sensory domains, although olfactory, tactile, and gustatory hallucinations are less typical of psychiatric illness. Hallucinations can be differentiated from illusions by having no basis in reality, whereas illusions are misperceptions of natural sensations. Delusions are fixed, false beliefs that persist in spite of contradictory evidence. Often, delusions are paranoid (e.g., a feeling of being watched or followed) or grandiose (e.g., possessing special powers or relationships with powerful people). Hallucinations and delusions must be considered within the relevant cultural context.

The lifetime prevalence of psychosis is between 3% and 5% in the general population. Most cases of psychosis are due to causes other than schizophrenia. The majority of nonschizophrenia psychosis is seen in drug-induced psychosis, mood disorders, and general medical causes.

SCHIZOPHRENIA AND OTHER PSYCHOTIC DISORDERS

EPIDEMIOLOGY

Globally, estimates suggest that almost 1% of the population will develop schizophrenia in their lifetime. The typical age of onset of schizophrenia is the late teens or early 20s, with men diagnosed on average a few years younger than women. Most people who develop schizophrenia have a prodromal period of illness before they meet the threshold for diagnosis characterized by subthreshold psychotic symptoms in conjunction with declines in social and occupational functioning. Schizophrenia typically follows a relapsing and remitting course characterized by periods of stability with episodic exacerbations of symptoms. Although antipsychotic medications are efficacious in reducing psychotic symptoms, many individuals may still have symptoms despite usual treatment.

NEUROBIOLOGY

Scientists debate whether schizophrenia is a degenerative brain disease, neurodevelopmental disease, or a combination of both. Several studies have shown that there are neuroanatomic differences in ventricle size, cortical thickness, gray and white matter, and overall brain volume in people with schizophrenia. Supporting neurodevelopmental hypotheses, neuroanatomic differences are seen before the onset of psychosis. However, favoring degenerative hypotheses, these differences increase over the course of illness. Further, although many studies have shown that cognitive decline predates the onset of psychosis, there is some evidence that cognitive deficits worsen over time. It is difficult to isolate a specific degenerative impact of schizophrenia itself apart from other environmental factors such as chronic exposure to antipsychotic drugs.

Much work has been done to isolate the specific neurotransmitter systems responsible for psychosis and schizophrenia. Although no single system is responsible for the overall psychotic phenotype, several have been shown to contribute to the development of symptoms. Dopamine is often most closely associated with psychosis and all currently marketed antipsychotic drugs are dopamine D2 antagonists but those drugs do not address all facets of the illness. Other neurotransmitters implicated include serotonin, glutamate, and acetylcholine.

CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

Schizophrenia is a serious mental illness responsible for significant morbidity, diminished quality of life, loss of productivity, and premature mortality. There is a 5% to 10% risk of suicide, and schizophrenia is a leading cause of disability throughout the world. Symptoms of schizophrenia can be categorized into positive, negative, and cognitive domains. Positive symptoms refer to delusions, hallucinations, and disorganized speech or behavior. Negative symptoms include apathy and avolition and generally refer to deficits in functioning. Cognitive symptoms affect multiple domains including primarily executive functioning, verbal learning, and working memory.

Although schizophrenia cannot be diagnosed until psychosis has been present for at least 1 month, nonspecific symptoms have been seen from early childhood in people who later develop schizophrenia. For example, young children who go on to develop schizophrenia have increased incidence of deficits in motor skills compared to children who do not develop schizophrenia or other psychiatric disorders.

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), which was released in 2013, modified the criteria for psychotic disorders (Fig. 148.1). A schizophrenia diagnosis requires at least two out of five symptoms including hallucinations,
delusions, disorganized speech, disorganized behavior, or negative symptoms for at least 1 month and with an overall duration of illness of at least 6 months. New in DSM-5 is a requirement for hallucinations, delusions, or disorganized speech; only having disorganized behavior and negative symptoms does not meet the new criteria. If mood symptoms are present, a timeline is essential to determining the correct diagnosis. If there are concurrent mood symptoms along with the hallucinations or delusions, the criteria for schizoaffective disorder are met if the psychotic symptoms persist for at least 2 weeks in the absence of mood symptoms and if the mood symptoms are present for the majority of the entire illness. If the psychotic symptoms occur only in the context of a mood disorder (bipolar disorder or major depressive disorder), then the diagnosis is bipolar disorder or major depressive disorder with psychotic features. If the only psychotic symptom is a delusion, then the diagnosis may be delusional disorder, particularly if there is limited functional impairment. Catatonia is a constellation of psychomotor features that may include stupor, posturing, mutism, stereotypy, and other odd mannerisms. Catatonia is often associated with schizophrenia but can be present in most other serious mental illnesses. Catatonia is included in the DSM-5 as a specifier for several mental disorders and is seen in approximately 10% of patients hospitalized with schizophrenia.

FIGURE 148.1 Diagnostic algorithm for a patient with psychotic symptoms. (Based on American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013.)

Psychotic symptoms frequently occur in other psychiatric disorders. Up to 60% of people with bipolar disorder have a history of at least one psychotic symptom, and psychosis is seen in up to 50% of manic episodes. Psychosis may also be present in depression, especially when it is severe. Overall, people with depression are three times more likely to have hallucinations and nine times more likely to have delusions compared to those without depression. Up to 15% of people with schizophrenia have comorbid obsessive-compulsive symptoms. People with social phobia and general anxiety also have an increased incidence of psychosis. Data from the National Comorbidity Survey suggests that psychosis should
lead to a separate subtype categorization of PTSD and a subtype of “with dissociative symptoms” was added to DSM-5. Substance abuse and schizophrenia frequently co-occur, with rates of substance use disorders as high as 70% in people with schizophrenia. In a large European study of first-episode schizophrenia, already 31.1% of patients reported a comorbid substance use disorder, including 22.2% who used marijuana. Comorbid substance use is associated with poorer medication adherence, more hospitalizations, and overall worse functional outcomes, with the worst effects seen in heavy substance users.

SCHIZOPHRENIA-SPECTRUM CASE

A 21-year-old male collegian is brought to the student health service by his resident advisor (RA). The RA notes that over the past several months, the student has withdrawn from fellow students and stopped participating in dormitory activities. His grades have suffered, and he was caught smoking marijuana in his room. He recently began putting tape over the cameras in the computer lab and foil over the windows of his room. When asked about these behaviors, the student said that the Central Intelligence Agency (CIA) was tracking his movements through a vast network of computers. He spent several nights sleeping in the library or in a local 24-hour coffee shop to avoid detection. He believed that the CIA considered him to have special knowledge of operations within the government. The student believed that everyone knew about him because the CIA had put up a website about him. He said that he could hear agents and other people talking to him through the walls of his room, commenting on his behaviors, and telling him that he was stupid. His sleep was poor and he was using marijuana to help sleep and to manage his anxiety.

TREATMENT/OUTCOME

Antipsychotic Medication

The mainstay of treatment for schizophrenia and other psychotic disorders is antipsychotic medication. Antipsychotics reduce psychotic symptoms and reduce relapse rates [Level 1].1 All currently available antipsychotic medications antagonize dopamine D2 receptors in the brain, which is thought to be their primary mechanism of action. Historically, antipsychotic medications have been categorized based on their potency at the D2 receptor into high-potency and low-potency categories. Antipsychotics also affect other neurotransmitters including serotonergic, histaminergic, and adrenergic receptors. Effects on the various neurotransmitters determine therapeutic and adverse effects.

All antipsychotic drugs are capable of inducing neurologic side effects including abnormal involuntary movements known as tardive dyskinesia (TD), akathisia (restlessness), dystonia, and pseudoparkinsonism (tremor, rigidity, and bradykinesia) (Table 148.1). By definition, TD is associated with prolonged (at least 3 months) exposure to an antipsychotic agent. Increased age, female gender, and duration of exposure are the greatest risk factors for TD. Newer (or second-generation) antipsychotics tend to have lower risk of TD but risk varies according to individual drug characteristics, as well as dose and duration of exposure. Drugs with lower potency at the D2 receptor tend to be associated with more adverse metabolic side effects (weight gain, diabetes, dyslipidemia), whereas those with higher potency are more likely to cause neurologic side effects. Severe dystonias, especially those involving laryngeal or extraocular muscles, require emergency treatment with intramuscular diphenhydramine (50 mg) or benztropine (2 mg). Oral benztropine (1 to 4 mg daily) is effective for treatment of antipsychotic-induced tremors, and propranolol (30 to 90 mg daily) is often used for treatment of akathisia.

Metabolic side effects are closely associated with many antipsychotic treatments, in particular clozapine, olanzapine, quetiapine, and risperidone. The mechanism by which antipsychotics cause these effects is not conclusively known. Schizophrenia has long been associated, even before the introduction of antipsychotic medications, with increased rates of diabetes and obesity compared the general population. Clozapine, olanzapine, and quetiapine are potent antihistaminergic agents and thus are associated with drowsiness and central histamine H1 receptor activity, which may contribute to their risk of weight gain. Other theories regarding the metabolic effects focus on shared signaling pathways between insulin regulation and psychosis involving the kinase AKT1 in the brain, pancreas, and liver. Peripheral response to antipsychotic drugs may feedback to the brain in a way that alters insulin secretion, which may have effects on weight. Although diabetes may often result from the central adiposity associated with antipsychotics, there are likely multiple pathways responsible for these metabolic effects, as people may develop insulin resistance and diabetes in the absence of weight gain and vice versa.

A dangerous but rare side effect of antipsychotic drugs is neuroleptic malignant syndrome (NMS). NMS is characterized by tremors, muscle rigidity and myalgias, extreme fever, other autonomic instability, and altered mental status. The muscle rigidity ultimately leads to rhabdomyolysis, with increased creatine kinase (CK) and white blood cell counts. The resultant muscle breakdown products can lead to acute renal failure. Without rapid and intensive intervention, NMS can be fatal and is in nearly 10% of cases. Treatment of NMS focuses on stopping the antipsychotic immediately, cooling the hyperthermia rapidly, and protecting the kidneys from myoglobinemia through aggressive hydration.

Antipsychotics differ mainly in side effects, but some small to moderate differences in efficacy have also been detected. All three of the medicines with better efficacy that are available in the United States (clozapine, olanzapine, and risperidone) are associated with adverse metabolic effects. This finding leads to a clinical dilemma in which clinicians and patients must balance the opportunity for maximum symptom improvement with significant metabolic risk.

Clozapine has a special role because it is more efficacious than other antipsychotics in patients with treatment-resistant schizophrenia and has been shown to decrease suicidality and to cause the fewest abnormal involuntary movements. However, in addition to weight gain and significant metabolic side effects, clozapine is also associated with agranulocytosis and subsequent risk of death due to infection. Therefore, patients taking clozapine must be enrolled in a clozapine registry and monitored carefully for decreases in granulocyte counts. Other risks of clozapine include myocarditis and seizures. However, with close clinical monitoring, clozapine can be highly effective for many patients.

Nonpharmacologic Treatment

Nonpharmacologic treatments for schizophrenia that are supported by some evidence include repetitive transcranial magnetic stimulation (rTMS) for auditory hallucinations that do not respond to antipsychotic medications [Level 1].1 Several psychosocial treatments are effective for specific problems associated with persistent psychotic illnesses. For example, multidisciplinary teams known as Assertive Community Treatment (ACT) teams provide outreach and comprehensive care, which reduces rates of hospitalization [Level 1].2 Supported employment programs are effective in helping people with schizophrenia obtain jobs [Level 1].2

TABLE 148.1 Selected Information on Commonly Used Antipsychotics

Antipsychotic Medication	Haloperidol	Aripiprazole	Clozapine	Olanzapine	Paliperidone	Quetiapine	Risperidone	Ziprasidone	Lurasidone
Typical dose range for maintenance treatment of schizophrenia	Oral: 2-12 mg	Oral: 10-30 mg	Oral: 150-600 mg	Oral: 10-30 mg	Oral: 6-12 mg	Oral: 300-800 mg	Oral: 2-8 mg	Oral: 80-160 mg	Oral: 40-80 mg
Side Effect Risk
Akathisia/parkinsonism	+++	+	0/+	+	++	0/+	++	+	++
QT prolongation on ECG	+	+	+	+	+	+	+	++	0
Glucose abnormalities	+	+	+++	+++	+	++	+	0/+	+
Lipid abnormalities	+	+	+++	+++	++	++	++	0/+	+
Orthostatic hypotension	0/+	0/+	+++	++	++	++	++	+	0
Weight gain	0/+	+	+++	+++	++	++	++	0/+	0/+
Serum prolactin elevation	++	0	0	+	+++	0/+	+++	+	+
Sedation	+	+	+++	++	+	++	+	+	+
0, no or minimal risk; +, low risk/mild effects; ++, medium risk/moderate effects; +++, high risk/severe effects; ECG, electrocardiogram. Data from Stroup TS, Lawrence R, Abbas AI, et al. Schizophrenia spectrum and other psychotic disorders. In: Hales RE, Yudofsky SC, Roberts LW, eds. The American Psychiatric Publishing Textbook of Psychiatry. 6th ed. Washington, DC: American Psychiatric Publishing; 2014:173-206; and Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71-93.