Clinical manifestations

Presentation and course

Schizophrenia belongs to a larger group of psychotic disorders that are characterized by disturbances in cognition, perception, flow and organization of thought, and motor behavior. No single specific symptom is pathognomonic of the condition. The diagnosis of schizophrenia is made based on criteria defined in the DSM-5 (Table 1) and requires symptoms to have occurred for 6 months or longer. In contrast, brief psychotic disorder is defined by psychotic symptoms that are present for at least a day and up to a month. Symptoms that persist for at least a month, but not more than 6 months, are defined as schizophreniform disorder.

Table 1. Diagnostic Criteria for Schizophrenia, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition

Features are typically divided into “positive” and “negative’ symptoms. Positive symptoms are those that are absent in health, such as hallucinations and delusions. Negative symptoms are lacking or disrupted in disease but present in health and include changes in executive function, working memory, and attention.

Positive symptoms. Delusions are fixed, false beliefs that remain firm despite overwhelming proof in dispute. Delusional beliefs are outside the bounds of culture, such that religious beliefs held by a group of believers are not conceptually delusional. Delusions can vary in their themes, valence, and degree of implausibility (see Table 2).

Table 2. Common Types of Delusions

Hallucinations are perceptual experiences that occur without an external stimulus. Hallucinations can occur in any sensory modality (auditory, visual, tactile, olfactory, or gustatory). In schizophrenia, hallucinations are primarily auditory in nature as one or more voices that may or may not be familiar and are distinct from the individual’s thoughts. Classic descriptions of auditory hallucinations include a running commentary of multiple voices that are often derogatory in their content.

Other features of schizophrenia include disorganization of speech, which is believed to demonstrate disorganization of thought; hence, schizophrenia is designated as a “formal thought disorder” (Table 3).

Table 3. Features of Disorganization Noted in Speech in Schizophrenia

Disorganization can also be seen in motor behavior. Movements can be stereotyped (saluting, gestures) or nonspecific such as agitation, pacing, and childlike silliness. Catatonia is a complicated condition that is not specific to schizophrenia but can be associated with it. In this manifestation, patients show reduced or oppositional responses to environmental cues with motor symptoms that may include stereotypies, waxy flexibility, mutism, or stupor. (For more information, please see the Medlink article “Catatonia.”)

Negative symptoms. Much of the disability associated with schizophrenia can be attributed to negative symptoms, which are more prominent in schizophrenia than in other psychotic disorders. Negative signs and symptoms may include reduction or flattening of affect, decreased experience of pleasure (anhedonia), decreased motivation (avolition), and social withdrawal (asociality). The quality of speech can become more impoverished with decreased speech (alogia) and changes in prosody. Cognitive changes can be apparent and can include poor concentration, impaired working memory, and changes in executive function.

Course of illness. The signs and symptoms used to define schizophrenia are typically first observed in late adolescence/early adulthood, although the pathologic processes underlying the condition likely precede the clinical onset. Frequently, patients with schizophrenia first come to psychiatric care during an active phase of symptoms. However, observable changes in behavior often precede the active phase by several months, a phase known as the “prodrome” (62; see Table 4). Of those who present with prodromal symptoms, the conversion rate to schizophrenia is 35%. Seventy percent of individuals achieve full remission within 3 to 4 months, and 80% achieve stable remission in 1 year.

Table 4. Prodrome of Schizophrenia

An initial psychotic episode may be acute, lasting only a few days or weeks but may progress over years, the latter being a negative prognostic feature. Several longitudinal courses of the illness can be differentiated: continuous, episodic with remission, episodic with stable deficit, episodic with progressive deficit, complete remission, incomplete remission, course uncertain, or period of observation too short (ie, the course should not be stated unless there has been a period of observation for at least 1 year).

In most cases, nonspecific prodromal symptoms, such as concentration deficits, agitation, insomnia, anxiety, anhedonia, anergia, and social withdrawal, will be reported by the patient or his/her relatives. Presentation largely depends on which dimension of thought, behavior, or affect is predominantly affected. Better prognosis may be associated with acute onset, older age at onset, clarity in presenting symptoms, more positive than negative symptoms, identifiable and treatable triggers, social support, insight to disorder, and medication compliance.

Given the variety of symptoms that can be seen in schizophrenia, there has been some effort to delineate clinical subtypes. The assumption is that different symptom clusters can be differentiated and will have differential prognoses and different treatment responses. Understanding the subtype could then guide and predict treatment and be an explanation for the variability in the existing data. Indeed, several subtypes of schizophrenia were defined in DSM-IV and earlier editions, including paranoid, catatonic, simple, residual, and undifferentiated schizophrenia. However, there haven’t been enough data to support these clinical subtypes and the most recent edition of the DSM does not include subtypes, despite the hope that symptom clusters and subtypes may have utility in guiding pharmacologic treatment or understanding the etiology with further research.

Prognosis and complications

The course of schizophrenia can vary substantially and is difficult to predict. Some patients may suffer one or two psychotic episodes and never again relapse while adhering to medication, whereas others may be able to discontinue medication carefully without suffering a relapse. About 20% of individuals with schizophrenia will have a favorable course, and a subset of these seem to recover to premorbid state. However, the majority have a chronic, relapsing, remitting illness with progressive worsening of negative symptoms and relative reduction of positive symptoms with age. A proportion of these are chronically and severely impaired, requiring significant support at baseline. Patients who demonstrate significant grandiosity and less severe hallucinations may be more likely to relapse (47).

Suicidality. The most dangerous complication of schizophrenia may be an elevated risk for suicide. In a 1-year follow-up study of first-episode psychosis, 11% of individuals attempted suicide, with hallucinations and a history of prior suicide attempts being the strongest predictors of suicidal behavior (42). Other studies suggest that depressive symptoms are the strongest predictor of suicidal behavior in schizophrenia. Additional clinical features that increase suicidal risk are prior attempts of suicide, severity of psychotic symptoms (particularly hallucinations and thought insertion), panic attacks and other anxiety symptoms, poor treatment adherence, repeated brief hospitalizations, high premorbid intelligence, and early stage of the illness (53). A meta-analysis of observational studies revealed a pooled lifetime prevalence of suicide attempts as high as 26.8% (36). Risk factors included earlier age of onset and living in a higher-income country. In a longitudinal study starting at first episode, protective factors included employment and longer period of untreated illness. Substance use significantly increased the risk of suicide (51).

Alcohol use is a modifiable risk factor that increases the risk of suicide in schizophrenia. Alcohol use was associated with completed and attempted suicide as well as suicidal ideation in a meta-analysis of schizophrenia (40).

Suicidality may be associated with abnormal brain structure and connectivity in fronto-temporo-limbic regions. Subcortical structures, such as the amygdala, play an important role in emotion regulation, aggression, and impulse control. Right amygdala hypertrophy, found on structural MRI, was found to be a risk factor for suicide attempts and self-aggression in a cross-sectional case-control study of patients with schizophrenia (50).

Aggression and violence. Violence in people with schizophrenia is uncommon. However, paranoia and command hallucinations may precipitate aggression in individuals with schizophrenia, elevating risk above the general population. Prevalence of recent aggression among outpatients with schizophrenia is around 5%. The types of violence and aggression are classified as follows: verbal aggression (around 45%), physical violence towards objects (around 30%), violence towards others (around 20%), and self-directed violence (around 10%). Family members are involved in 50% of the assaults; strangers are attacked in 20% of cases. Assessing acute risk of harm to self or others is a necessary challenge for mental health providers.

Homelessness. Schizophrenia is a significant contributor to disability worldwide. Large studies of homeless populations have revealed that psychotic disorders, including schizophrenia, are overrepresented as compared to domiciled individuals. This was higher in developing countries, up to 22% (03).

Clinical vignette

Mr. R is a 22-year-old man who presented with a 7-month history of social withdrawal, eventually ceasing to attend his university lectures. Members of his household became worried when he put tin foil on his windows to stop what he described as “others hearing my thoughts.”

The month prior to admission, Mr. R became convinced that the government was conspiring to “get rid” of him. He says he realized this when he saw a girl with red hair and a red coat looking at him on the bus 2 months prior to referral to psychiatric services. He also felt the government could control his moods and, at times, his left arm. He was convinced this was because the government wanted to get rid of all students to avoid paying for their studies and, ultimately, to avoid being challenged by intellectuals. He heard voices of two male government officials for 6 weeks prior to referral, but he could not see anyone around when he heard them. The voices talked about him between themselves and made critical comments about him. He denied depression or suicidal or homicidal ideation.

Mr. R had no significant medical history. Developmental history was unremarkable. He had used cannabis occasionally in his teenage years, although not recently. He had a family history of an uncle who was “eccentric, with odd ideas about things” and talked to himself, but the uncle had no specific psychiatric diagnosis.

Examination was remarkable for a malodorous young male with a disheveled appearance, wearing sunglasses and a hat lined with tinfoil in the office. He demonstrated affective blunting, poor eye contact, and hand wringing. Laboratory and imaging studies were all within normal limits.

He was diagnosed with schizophrenia due to a greater than 6-month history of prodromal symptoms, including a month of active phase symptoms with delusions, hallucinations, and social withdrawal that impaired function. Presentation could not be explained by another mental disorder, substance, or medical condition.

He was started on olanzapine 5 mg, which was eventually increased to 10 mg, and he was monitored by the community psychiatric team. He responded well to the olanzapine, and his presenting symptoms remitted in a few weeks. However, he became distressed by weight gain and discontinued the medication and disengaged from community support. This, unfortunately, led to a relapse of symptoms and hospitalization.

In the hospital, he was started on aripiprazole, with the hope that this medication would have less impact on his weight, and he was given cognitive behavior therapy to help him understand and make sense of his delusions and hallucinations when his mental state improved. Staff thoroughly explained the purpose and importance of medication. He was given diet and exercise advice and appropriate psychosocial support in the community. He subsequently returned to college.

Biological basis

Etiology and pathogenesis

It is generally agreed that schizophrenia is a multifactorial illness involving genetic and environmental interactions that result in alterations in synaptic plasticity, dendritic spine density, and synaptic transmission. Genetic vulnerability is shared in part with bipolar disorder, as well as developmental disorders such as autism (56). Table 5 describes the most commonly recognized risk factors for developing schizophrenia.

Table 5. The Common Risk Factors for Schizophrenia

Although the population risk is around 1%, Gottesman’s twin and family studies demonstrate that the degree of risk correlates highly with the genetic relatedness (17). The highest risk of schizophrenia is in the offspring of two parents with schizophrenia (46%) and in monozygotic twins (48%) as compared to dizygotic twins (17%). Because dizygotic twins have almost double the risk of non-twin siblings, but on average similar genetic relatedness as non-twin siblings, shared early environment also affects risk.

The etiology of schizophrenia is complex and currently lacks a unifying mechanism to account for the signs and symptoms that are used to define the condition. Information to understand the pathogenesis has been derived from observational and heritability studies, functional imaging, and animal models.

Despite evidence for heritability, intensive genetic investigations have not identified a single “schizophrenia gene.” Rather, polymorphisms of certain genes seem to influence the susceptibility for the illness. Promising candidate genes include dysbindin, neuregulin, G72 (DAOA), the COMT gene, and others. Most of these polymorphisms have functional effects on brain maturation, synaptic transmission, and plasticity, and they probably lead to alternations in neurodevelopment (19).

Biological and morphological findings in patients with schizophrenia include widespread alterations in multiple regions, including the limbic system, frontal cortex, temporal lobe, and basal ganglia. A meta-analysis of cortical thickness throughout the whole brain in patients with schizophrenia, from first episode to chronic schizophrenia, as compared to healthy controls demonstrated reduced cortical thickness only in chronic schizophrenia in the right inferior frontal gyrus, bilateral insula, and superior temporal gyrus (52).

Reduced functional connectivity between different brain areas has been found as measured by fMRI (32). Global and regional white matter volumes in the prefrontal cortex (61) and prefrontal cortex cerebral blood flow as measured by fMRI have been shown to be reduced (20), referred to as hypofrontality. Several PET and SPECT studies have shown a pronounced increase of amphetamine-induced dopamine release, indicating a dysregulation of dopaminergic transmission (07). A meta-analysis examining resting-state fMRI in individuals at a clinically high risk of psychosis, including first-degree relatives or those with mild psychotic symptoms revealed significant hypoconnectivity, suggested that large-scale network dysfunction underlies the cognitive and perceptual disturbances in patients with schizophrenia (13).

Deficits in social cognition may be related to differential brain activation in schizophrenia as compared to health controls. A meta-analysis of existing neuroimaging data examining the neural correlates that underlie theory of mind and empathy demonstrated decreased right ventrolateral prefrontal cortical brain activation in tasks involving emotional attribution and reduced left posterior temporo-parietal junction in intention/belief attribution tasks, suggesting a role for these regions in verbal auditory hallucinations and patterns of attributions (59).

The basis for these brain abnormalities may either lie in abnormal development, degeneration of neurons after development, or both. Many subtle cognitive, motor, and behavioral changes are seen years before illness onset (24). Some developmental genes—including those identified as schizophrenia susceptibility genes—influence brain development at sequential stages, as reported from postmortem human brain and developmental animal studies (12). MRI studies suggest that the ventricular enlargement is not progressive, indicating an apparently static lesion of the brain. There is no evidence of an ongoing degenerative process, as would be indicated by reactive gliosis.

The most convincing etiologic theories postulate that a polygenetically determined disturbance of synaptic neurotransmission leads to the destruction of neuronal circuits. It has been proposed that deficits of glial growth factors resulting in disturbed neurogenesis, migration, and cell differentiation lead to glial depletion and, thus, to reduced synaptic stability (39). From a molecular genetic point of view, it has been hypothesized that single nucleotide polymorphisms (SNPs) in genes that modulate glutamatergic synaptic formation lead to disturbed plasticity and signal transduction. A disturbance of glutamatergic neurotransmission, therefore, might lead to reduced neuronal connectivity (18).

Epidemiology

The onset of symptoms typically occurs in young adulthood, with a global lifetime prevalence of about 0.3% to 0.7%. The incidence of the disorder varies greatly across places and migrant groups, as do symptoms, course, and treatment response across individuals (56). This is in contrast to the Epidemiologic Catchment Area study, which found that the lifetime prevalence of schizophrenia is about 1% worldwide and that schizophrenia does not depend on social background or geographical origin. Illness onset is earlier in male patients, occurring between ages 15 and 24 years, whereas in women onset is typically between 25 and 35 years of age.

Prevention

Thus far, there are no identified unambiguous risk factors that allow for effective prevention strategies. Individuals at risk for developing schizophrenia (eg, those with a positive family history) may precipitate the onset of symptoms with cannabis abuse, which seems to constitute an independent risk factor for developing psychosis or schizophrenia. A meta-analysis on the association of cannabis use and schizophrenia suggests that especially early use of cannabis increases the risk of psychosis, with a dose-related effect on psychotic symptoms (49). Cannabis use also has been associated with earlier onset of schizophrenia in young men (57). Consequently, the only preventative strategy known is abstinence from cannabis.

Differential diagnosis

The differential diagnosis for acute psychosis is broad and includes psychiatric illnesses, intoxication, and a variety of medical conditions (see Table 6). Younger patients who present with symptoms of psychosis and without comorbid medical or psychiatric symptoms or exposures are less complicated to diagnose. However, often patients present for care at middle or older age with little known medical history and no available collateral informants, and they are unable to give a cogent history. At these times, history of schizophrenia may not be known and the differential for presenting symptoms is widened.

Table 6. Differential Diagnoses for Schizophrenia

Psychotic symptoms, such as delusions or hallucinations, are present in a variety of psychiatric disorders, such as severe unipolar and bipolar affective disorders. However, in these disorders, the affective symptoms are prominent, and there are no psychotic symptoms in the absence of mood symptoms. Psychotic symptoms are typically mood-congruent.

In schizoaffective disorder, symptoms of a major mood episode co-occur with schizophrenia criterion A (two or more positive or negative symptoms). However, criterion A symptoms must also be met and present for at least 2 weeks without the main criteria for mood disorder.

Brief psychotic disorder includes psychotic symptoms for greater than 1 day, but less than a month with return to normal functioning. Because the time course of schizophrenia requires symptoms for greater than 6 months, patients with symptoms greater than a month, but less than 6 months, are diagnosed with schizophreniform disorder, which often persists and is amended to schizophrenia with continued illness.

Schizotypal personality disorder is characterized by eccentric behavior and anomalous thought content, without other main symptoms such as hallucinations or delusions. Delusional disorder is defined by a fixed false belief or beliefs that persist greater than a month, without meeting criterion A. The condition may have functional impact regarding the specific delusions, but the patient is otherwise without impaired.

Trauma-based disorders, such as posttraumatic stress disorder (PTSD) and borderline personality disorder, can demonstrate paranoia and hallucinations stemming from exposures to dangerous situations and may be a manifestation of severe hypervigilance.

Certain dementing illnesses, such as synucleinopathies (diffuse Lewy body dementia and Parkinson dementia), Alzheimer disease, and occasionally, vascular disease, can have psychotic symptoms.

Medical causes of psychosis are also varied. Intoxication with hallucinogens, stimulants, and even alcohol can lead to psychotic symptoms. GABAergic withdrawal can result in hallucinations and delusions. Delirium, which is a waxing and waning attention caused by an underlying metabolic, pharmacologic, infectious, or inflammatory process, can also display psychotic symptoms. Other conditions, including idiopathic and iatrogenic hormonal imbalance, seizures, systemic autoimmune diseases such as lupus or autoimmune and other encephalitides, and paraneoplastic syndromes might mimic an acute psychosis with hallucinations, delusional thinking, agitation, and anxiety. However, in these cases, a medical factor will be identified with thorough physical examination, urine drug screening, laboratory blood analysis, imaging, and EEG.

Diagnostic workup

Diagnosis is based on a thorough clinical interview and medical history, laboratory screening, and observations of behavior, as well as collateral information from relatives or other persons in close contact. Specific attention is paid to all available relevant information concerning the first occurrence of psychotic symptoms, changes in behavior, and deterioration of social functioning and ability. Any severe somatic conditions need to be ruled out (eg, acute or chronic inflammation or other damage of the brain, hormonal disturbances, intoxications, and other relevant laboratory disturbances). The role of imaging in first-break psychosis is of question. The value of imaging likely increases in cases that are outside the typical age of onset or have high burden or focal neurologic symptoms.

Diagnostic criteria as defined by DSM-5 are described in Table 1. Standardized diagnostic interviews and scales, eg, the Positive and Negative Symptom Score (PANSS), can quantify the severity of the episode.

Management

Adequate pharmacological treatment is the first line of treatment strategy and represents the basis of all subsequent social and psychotherapeutic interventions. Because longer duration of untreated illness is associated with greater treatment resistance, more severe positive and negative symptoms, and worse functional outcome (44), psychopharmacological treatment should be implemented as early as possible.

The disability of schizophrenia both in acute and long-term phases can be considerable. Self-neglect, apathy, and disability derived from negative symptoms and cognitive dysfunction require social care and support as a central part of services. Community mental health teams and assertive community teams as well as rehabilitation teams provide important support to vulnerable individuals. Early intervention teams focus specifically on new-onset psychosis and reducing its impact biologically, psychologically, and socially (08).

Most medications used to treat schizophrenia are dopamine receptor type 2 (D2) receptor antagonists (antipsychotics or “neuroleptics”). Although the precise mechanism of action that accounts for the effects of antipsychotic medications is still unknown, it is thought that the reduction of dopamine in the mesolimbic dopamine pathway accounts for amelioration of positive symptoms.

There are two main categories of antipsychotics, the older “typical” antipsychotics and the newer “atypical” antipsychotics. Typical antipsychotics were first developed in the 1950s and are efficacious at reducing the positive symptoms of schizophrenia but have minimal effects on negative symptoms. Traditional antipsychotics are further subdivided by their potency (amount needed for effect) and are described as low, mid, and high potency. Low-potency antipsychotics (eg, chlorpromazine) also tend to block muscarinic cholinergic receptors, leading to anticholinergic side effects (sedation, dry mouth, weight gain), whereas high-potency antipsychotics (haloperidol, fluphenazine) are more likely to produce extrapyramidal effects such as parkinsonism, acute dystonia, and akathisia. Dystonia and parkinsonism can be ameliorated by adding an anticholinergic agent such as benztropine or trihexyphenidyl. Akathisia can be treated with a beta blocker or low-dose benzodiazepine if not contraindicated.

Most side effects of conventional antipsychotics are reversible on discontinuation. Tardive dyskinesia is one consequence of antipsychotic use that may become permanent and difficult to treat. Tardive dyskinesia often manifests as involuntary disfiguring oral-buccal, upper extremity, or truncal choreiform movements. These movements may go unnoticed by the patient. Vesicular monoamine transporter inhibitors (VMAT2), such as valbenazine and deutetrabenazine, have been developed to address the effects of tardive dyskinesia by depleting presynaptic dopamine (41).

Typical antipsychotics are effective at treating positive symptoms of schizophrenia. However, they block D2 receptors globally, including in the nigrostriatal pathway (causing extrapyramidal effects), the tuberoinfundibular pathway, leading to prolactinemia, resultant decreased libido and galactorrhea, as well as the mesocortical dopamine pathway, blunting cognition, which already may be impaired by the primary schizophrenic process.

Other neurotransmitters implicated in schizophrenia include serotonin and glutamate. The second generation, or atypical antipsychotics, have action on serotonergic receptors with blockade of the serotonin 2A (5HT2A) receptors. Atypical antipsychotics seem to have more impact on negative symptoms of schizophrenia as compared to typical antipsychotics. Blocking serotonin in the mesocortical dopamine pathway may reciprocally enhance dopamine release in the prefrontal cortex, thereby improving cognition.

The first atypical antipsychotic, clozapine, was discovered in the 1950s but was not introduced clinically for 2 decades. Clozapine is the most efficacious antipsychotic; however, its use is limited by life-threatening agranulocytosis, as well as toxic megacolon. Hoping to replicate the efficacy of clozapine, olanzapine, risperidone, and quetiapine were introduced into the market in the 1990s. Aripiprazole, lurasidone, ziprasidone, paliperidone, iloperidone amongst others, have been approved for the treatment of schizophrenia. Atypical antipsychotics are considered as first-line treatment for schizophrenia and are gradually replacing typical antipsychotics in frequency of use. In contrast to first-generation antipsychotics, treatment with atypical antipsychotics increases the risk of weight gain and metabolic syndrome (33). Less common side effects of include agranulocytosis, orthostatic hypotension, and some extrapyramidal side effects.

The advent of atypical antipsychotics was heralded with the hope that these medications would be superior to conventional antipsychotics both in terms of efficacy and side effect profile. Atypical antipsychotics do have some advantages over traditional antipsychotics including fewer anticholinergic and extrapyramidal side effects, as well as improvement in negative symptoms.

Unfortunately, despite the reduction (but not elimination) of extrapyramidal effects and tardive dyskinesia risk, atypical antipsychotics can have unfavorable metabolic alterations such as dyslipidemia, glucose level increases, altered insulin receptivity, body weight gain, and worsening cardiovascular risk profile. A meta-analysis of the comparative impact of antipsychotics on metabolic function revealed that greater increases in glucose were found in males and those with higher baseline weight (45). Increased total cholesterol was associated with nonwhite ethnicity. Of the antipsychotics examined, the worst offenders were olanzapine and clozapine, in contrast to aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone, as conferring the least metabolic derangements (45). Adjunctive metformin may be helpful in reducing metabolic parameters including weight, fasting glucose, and total cholesterol, though the impact on low-density lipoprotein cholesterol may not be significant (22). Patients who were metabolically normal prior to antipsychotic administration typically had greater metabolic effects, suggesting that baseline characteristics may not mitigate the risk of metabolic side effects (63).

A meta-analysis of 52 randomized trials (pooled responses of 12,649 patients on antipsychotic medication), comparing those on atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with those on typical antipsychotics (haloperidol and chlorpromazine) did not demonstrate superiority of atypical as compared to typical antipsychotics (16). Although drug-induced movement disorders have dramatically declined with widespread use of second-generation antipsychotics, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial highlights that the advantages of second-generation antipsychotics in significantly reducing extrapyramidal side effects compared with haloperidol may be diminished when compared with modest doses of lower-potency first-generation drugs (09).

The differential effects on quality of life, adverse effects, sufferer satisfaction, and cost of care between typical and atypical antipsychotics might be smaller than expected (23). All antipsychotics can produce side-effect profiles that can undermine compliance and care, especially in an individual who already could be skeptical of the diagnosis. In a long-term ambulant setting, noncompliance rates of 64% to 82% with respect to discontinuation of classical and atypical antipsychotic medication have been reported (see Table 7) (34).

When symptoms are refractory to treatment, one can consider an antipsychotic with a different receptor binding profile. After treatment failures with typical and atypical agents, clozapine should be considered. Most clinicians do not use clozapine as a first-line agent due to the rare but significant adverse effects, including agranulocytosis, reduced seizure threshold, toxic megacolon, and myocarditis with the potential of death. Treatment is guided by a registry and requires frequent blood draws for medication dispensation (weekly for the first 18 months of treatment, then monthly). Clozapine should be withdrawn whenever the neutrophil count falls to less than 500 per ml. Informed consent of the patient is a prerequisite for the treatment. Despite the risks, the impressive efficacy with lack of extrapyramidal effects and dyskinesia as compared to all other antipsychotics renders it one of the most useful antipsychotics in refractory cases. Newer data suggest that the benefits of clozapine may outweigh the risks. In refractory individuals, that rate of all-cause mortality is higher for patients not receiving clozapine as compared to those on clozapine (hazard ratio 1.88) that was driven by an increase compliance. Patients on clozapine also demonstrated less self-harm than other patients (60). The benefit of clozapine may be related to continuous use, with benefits seen at a median of 6.7 years (58).

Another strategy to target negative symptoms has been the addition of an augmenting agent. Varenicline, modafinil, and dopamine enhancers, such as agonists and stimulants, have not been shown effective in improving cognitive function in schizophrenia. There are promising data suggesting improvement in cognition with the NMDA-receptor antagonist, memantine augmentation (64). In severe cases, two antipsychotics may be combined. Although monotherapy has been primarily recommended, there is emerging evidence for increased efficacy and tolerability of antipsychotic polypharmacy, with the best evidence for the combination of clozapine and aripiprazole (04).

Due to the risks of tardive dyskinesia and parkinsonism with conventional antipsychotics, researchers are pursuing compounds directed at other transmitter systems with little to no activity at dopamine receptors. Compounds target the 5HT-2A receptor (pimavanserin) as well as impact muscarinic transmission, such as xanomeline-trospium, a muscarinic-1 and -4 receptor agonist combined with a peripherally restricted muscarinic antagonist to mitigate systemic adverse reactions (25). This combination was effective in reducing positive and negative symptoms of schizophrenia in a double-blinded placebo-controlled trial; common side effects include anticholinergic effects, such as constipation, nausea, and dyspepsia.

After the first psychotic episode, medication should be continued for at least a year. A 10-year follow-up study of a randomized controlled trial of first-episode patients with full symptom reduction after a year of treatment examined the long-term consequences of discontinuing antipsychotic medication (21). A poor outcome was more likely in the discontinuation group (risk ratio of 1.84; confidence interval 1.15-2.96) with a recommendation to continue an antipsychotic for at least 3 years after the first episode. Stable patients should be maintained on the lowest possible effective dosage of medication. Subsequent episodes of psychosis likely prognosticate needing to be on medication indefinitely; however, dose reductions can be attempted after prolonged periods of stability and under close observation.

There have been attempts to target patients at risk for psychosis or after their first psychotic episode with agents either to target progression to psychosis or ameliorate severity of illness. Initial studies of omega-3 fatty acids in at-risk individuals demonstrated encouraging results in reducing transition to psychosis or maintaining cortical integrity; however, this has not been borne out in larger studies. A systematic review of adjunctive nutrients in first-episode psychosis suggests that taurine and n-acetyl cysteine may reduce symptom burden, possibly through antioxidant mechanisms (15). Participation in services targeted at phase-specific treatment of the first episode, known as early psychosis intervention, may improve mortality rates and improve outcomes (02). Further research is needed in this area.

Patients who are nonadherent to oral medication should be offered a depot application (long-acting injectable form) of medication. Depot applications are available for the typical antipsychotics (fluphenazine, haloperidol) and for some atypical antipsychotics (risperidone, olanzapine, paliperidone, and aripiprazole). An examination of long-acting injectable paliperidone in recent-onset schizophrenia demonstrated decreased hospitalization and reduced total healthcare dollars, suggesting this strategy may be considered prior to evidence of nonadherence (05). A meta-analysis of effectiveness and efficacy trials of antipsychotics suggest that long-acting injectables perform better in the real world than indicated is in randomized controlled trials, further reinforcing their use in patients who are willing to take them (14).

Another accepted and well-tolerated option in treatment-refractory illness and in acute catatonic schizophrenia is electroconvulsive therapy, the induction of a seizure through external applications of electrodes under general anesthesia. Typically, patients undergo an index course of three treatments per week for 6 to 12 treatments (or until symptom remission) and may include periodic maintenance treatments to prevent recurrence. Common side effects are headache and paroxysmal decrease of short-term memory, which typically recover after terminating therapy (06). There are some cases of persistent changes in both retrograde and anterograde memory. Although prospective, controlled data are limited, the side effects profile of electroconvulsive therapy in combination with antipsychotics does not differ from that seen under antipsychotics alone. A randomized, double-blinded, sham-controlled study of repetitive transcranial magnetic stimulation (rTMS) using high-frequency stimulation over the left dorsolateral prefrontal cortex improved negative symptoms as compared to the control group (31).

Table 7. Dosage and Side Effect Profile of Different Antipsychotic Regimens for Treating Schizophrenia

Neuroleptic malignant syndrome is a rare but lethal consequence of antipsychotic administration and is characterized by rigidity, hyperthermia, confusion, diaphoresis, autonomic instability, and lab abnormalities including leukocytosis and elevated creatine phosphokinase. It is critical that neuroleptic malignant syndrome is recognized. Treatment includes the discontinuation of the offending agent and supportive care. Agents such as the skeletal muscle relaxant, dantrolene, or dopamine agonists like bromocriptine, can be tried adjuncts. Antipsychotics should be avoided for a few weeks after resolution of the episode; however, due to the nature of schizophrenia, it is unlikely that they can be permanently avoided.

Along with the acute treatment and intervention strategies, patients should be offered psychoeducation, occupational therapy, cognitive therapy, and other methods to regain structure of their daily activities. Patients should urgently be advised not to consume any recreational drugs. Psychotherapeutic interventions frequently focus on helping patients identify and achieve their personal goals while coping with the disease. Although, employment rates are low among the severely mentally ill, there is evidence that supported employment in a cohort of clients with first-episode psychosis was an independent predictor of vocational recovery in the following 12 months (37). Cognitive, behaviorally oriented service seemed to be beneficial in reducing early negative symptom exacerbations when compared to treatment as usual (27).

Although medication and electroconvulsive therapy are the primary treatment modalities for schizophrenia, there is increasing interest in using novel cognitive training approaches. Cognitive symptoms are generally more difficult to target with pharmacotherapy. Neuroscience-informed cognitive remediation can occur remotely, which has implications for the ability to distribute the technology. Auditory processing training for 40 hours, as compared to video game controls, demonstrated improved global cognition and problem-solving ability and a decrease in positive symptoms (35). The improvements were found to be sustained at a 6-month assessment. Patients engaged in 20 or 40 hours of auditory or visual training demonstrated improved emotion processing and social cognition, though symptoms were unchanged (48). Atlhough these computer-based treatments have the advantage of being free of metabolic and extrapyramidal side effects, they do require effort and motivation to complete, which may limit their use.

For the prodrome of schizophrenia following interventions are considered appropriate:

Outcomes

A Cochrane review of 75 randomized controlled trials concluded that maintenance treatment with an antipsychotic significantly prevented relapse as compared to placebo for up to 2 years of follow-up, with a trend toward increased quality of life. However, antipsychotics as a group were associated with an increased risk of adverse effects, including extrapyramidal symptoms and metabolic changes (10).

Patients with schizophrenia die an estimated 10 or more years earlier than the life expectancy of nonaffected patients. Suicide is a major cause of death, but the gap is also likely multifactorial. As compared to controls, a meta-analysis revealed that patients with schizophrenia are at increased risk of stroke and stroke-related complications, including mortality, suggesting interventions for primary prevention and mitigation of neurovascular risk factors (11).

Special considerations

Pregnancy

Generally, the use of psychotropic medication during pregnancy is indicated when risk to the fetus from exposure to medication is outweighed by the risk of untreated psychosis in the mother. Data from large health surveys indicate that antipsychotic medication confers no or only small risk for organic malformation. Findings in the published literature on the safety of antipsychotic medication are limited but encouraging (55). For atypical antipsychotics, a study of the effects of different atypical antipsychotics on rates of major malformation, spontaneous abortion, and stillbirth, as well as birth weight and gestational age at birth, did not reveal significant differences between mentally ill women who were treated with atypical medication versus mentally healthy women in any of the outcomes, except a higher rate of low birth weight in the offspring of women on medication (38). Continuation of olanzapine and quetiapine in pregnancy are associated with increased risk of gestational diabetes, as compared to those who discontinued use. This is likely related to the known metabolic side effects of these drugs (43). Given the lack of controlled, prospective studies, the clinician needs to weigh the substantial risk of untreated psychosis with the potential risk of the medication.

Anesthesia

Patients with schizophrenia may have a higher risk of developing cardiovascular disease, often suffer from silent cardiovascular infarction, show increased sensitivity to the hypotensive effects of anesthesia due to antipsychotic medication, and may be less sensitive to postoperative abdominal pain (28). The latter is especially important because postoperative paralytic ileus is a serious side effect frequently encountered in schizophrenic patients (29). There are only limited data on continuation of antipsychotic medication preoperatively, but patients who discontinued antipsychotic medication preoperatively, significantly more frequently suffered from postoperative confusion as compared to patients who continued their medication (30), whereas frequency of intraoperative hypotension and arrhythmia did not differ between groups. It is recommended to continue antipsychotic medication perioperatively.