Schizophrenia

Etiology

Multifaceted interactions between genetic and environmental risk factors give rise to schizophrenia. These risk factors also affect early brain development and shape the biological response to life experiences, thereby influencing the onset and progression of the disorder.[9]

Twin and family studies indicate that genetic factors can explain approximately 80% of the risk for schizophrenia.[1] While linked common genetic variants have less impact on risk, rare mutations have a more significant impact.[10] One such rare mutation is the chromosome 22q11.2 deletion, which increases lifetime risk 25-fold.[4] Genome-wide association studies have identified 130 genes predominantly associated with neural differentiation, organization, and transmission, which increase the risk of schizophrenia.[11] Most of these genes are not found in coding regions but exert their influence through gene expression modulation.[11] Notably, nearly 30% of these genes are involved in the functioning of the presynaptic and postsynaptic elements of the glutamatergic synapse by impacting N-methyl-D-aspartic acid (NMDA) receptor transmission.[11] Thus, schizophrenia is a polygenic disorder resulting from the combined effects of multiple genes spread across the genome, each contributing modestly.

The approximately 60% concordance rate for schizophrenia in monozygotic twins highlights the substantial role of environmental factors in shaping the expression of genetic risk for the disorder.[11] Environmental influences, such as complications during childbirth, early-life adversities, growing up in urban settings, and migrant status, are thought to interact with genetic predispositions to affect the likelihood of developing schizophrenia.[1][9]

Patients with schizophrenia exhibit both structural and functional brain abnormalities. Lateral ventricle enlargement by about 25%, coupled with an approximate 2% reduction in overall brain volume, primarily in the grey matter, is seen in schizophrenia.[1] This decrease in grey matter is noted predominantly in the frontal and temporal lobes and the hippocampus. There is evidence of reduced activity in the dorsolateral prefrontal cortex both at rest and during executive tasks, along with increased activity in the medial frontal cortex.[2]

The use of cannabis or its psychoactive ingredient, tetrahydrocannabinol (THC), is known to induce temporary psychotic effects. THC may exacerbate preexisting psychotic conditions and is a risk factor for schizophrenia. Studies indicate a heightened schizophrenia risk among young cannabis users and heavy cannabis users, with the risk seeming dose-dependent and more pronounced in those who begin using at an earlier age or consume more potent strains.[4] In one study, heavy cannabis users were at 6 times greater risk than nonusers of receiving a diagnosis of schizophrenia.[12] 

Several neurotransmitter systems have been implicated in the development of schizophrenia, with the dopaminergic and glutamatergic systems the leading contenders.

The neurodevelopmental hypothesis of schizophrenia proposes that a mix of genetic risks and environmental factors during early brain development leads to the disorder. These influences, particularly significant in the prenatal and early life stages, set the stage for the emergence of symptoms of schizophrenia in early adulthood.[13]

Epidemiology

The lifetime risk of developing schizophrenia is around 1%. Men are more likely to receive the diagnosis than women, with an incidence rate ratio of approximately 1.7 (95% CI, 1.46–1.97).[2][14] In men, the peak incidence is in the early twenties and then declines; women have a peak incidence later in their twenties, with a slower decline in incidence. Notably, after the mid-forties, new schizophrenia diagnoses become more common in women than in men.[2] Men typically exhibit an earlier onset of the disease, poorer functioning before the illness becomes apparent, more pronounced negative symptoms, and a higher incidence of alcohol and substance use disorders.[15][16] While gradual onset during adolescence is common, childhood-onset schizophrenia, defined as younger than 13 years, is rare and typically represents a more severe form of the illness with a poor response to antipsychotic medication.[17] Additionally, a higher rate of schizophrenia is linked to urban living and migrant status.[2]

Pathophysiology

Multiple molecular and neural circuit changes are linked to schizophrenia's pathophysiology, but whether these changes are direct causes or adaptive responses to upstream dysfunctions is unclear.[5] No present model of the pathophysiology of schizophrenia can comprehensively explain all the changes observed.

Neurotransmitter abnormalities are central to the pathophysiology of schizophrenia, with dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA) all playing roles.[1] The link between dopamine and schizophrenia emerged from the accidental discovery of dopamine D₂ receptor blockers' effectiveness in alleviating psychotic symptoms.[1] Four key dopamine pathways have been identified in the brain: mesolimbic, mesocortical, tuberoinfundibular, and nigrostriatal.[18] Excessive dopamine activity in the mesolimbic pathway, which runs from the ventral tegmental area to the limbic regions, is thought to contribute to the positive symptoms of schizophrenia. Reduced dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, may underlie negative symptoms and cognitive deficits.[19] These observations suggest distinct pathophysiological mechanisms for schizophrenia's positive and negative symptoms. Additionally, the nigrostriatal pathway is linked to extrapyramidal motor side effects caused by D₂ receptor blockers, while the tuberoinfundibular pathway is associated with the hyperprolactinemia observed with D₂ receptor blocker use.

Recent advancements in cognitive neuroscience have elucidated the activation of mesostriatal dopamine neurons in response to "reward prediction error," a phenomenon describing the mismatch between anticipated and actual rewards.[20] This dopaminergic activity is crucial in assigning "salience" to environmental stimuli, a process integral to learning and updating our internal model of the external world. In schizophrenia, there is a noted dysregulation in the firing of these neurons, which leads to a decoupling of dopamine signaling from genuinely salient stimuli, resulting in the misattribution of importance to irrelevant objects or events. This aberrant salience processing plays a significant role in the emergence and persistence of delusions and possibly hallucinations in schizophrenia, as patients might assign undue significance to neutral stimuli.[20]

Understanding dopamine's role in schizophrenia extends beyond the traditional dopamine hypothesis. There is a 2- to 4-week delay between antipsychotic medications' peak blockade of D₂ receptors and the clinical response.[1] This suggests that the antipsychotic effects of these drugs might depend on secondary neurochemical mechanisms triggered by sustained D₂ receptor blockade rather than reduced dopamine transmission alone.[1]

Moreover, the interplay between dopamine, glutamate, and GABA is critical in modulating the function of excitatory and inhibitory interneurons within cortical circuits. Postmortem studies indicate alterations in the microstructure and functioning of these microcircuits in schizophrenia. These findings have steered researchers towards exploring the potential of targeting glutamate and GABA signaling pathways in addition to dopamine for more effective therapeutic interventions in schizophrenia.[1][19]

History and Physical

History

In diagnosing schizophrenia, the patient is evaluated by taking a comprehensive history and conducting a mental status examination. Assessing risks of harm to oneself or others and considering the influence of substance use are critical components of this assessment. Collateral information from family members or close contacts is essential. The primary objective is to eliminate the possibility of other medical or psychiatric conditions presenting similarly and confirm the diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., Text Revision (DSM-5-TR), or the International Classification of Diseases, Tenth Revision (ICD-10) criteria.

The following are essential elements of history-taking:

1. History of present illness: Details of the chronology of symptom presentation and predisposing, precipitating, and perpetuating factors. A review of psychiatric symptoms and comorbid diagnoses is conducted. One should obtain a relevant negative history that could help differentiate schizophrenia from other medical or psychiatric conditions.
2. Past psychiatric history: This encompasses recording previous manic and depressive episodes, hospitalizations, treatments (including electroconvulsive therapy), adherence to treatments, the effects and adverse effects of medication, and any history of suicidality (ideas, plans, or attempts, including details), self-injury, and aggressive ideas or behavior.
3. Substance use history: The patient’s use of tobacco, alcohol, other substances, and prescription medications is documented.
4. Medical history: One should record the patient’s current medical conditions, medications, allergies, medical illnesses, treatments, surgeries, parity, and other relevant health information, such as neurological conditions and sleep issues. The clinician should review potential organic causes of psychosis, including Parkinson disease, multiple sclerosis, syphilis, HIV/AIDS, brain lesions, heavy metal toxicity, delirium, metabolic/endocrine disorders, and dementias, such as Alzheimer disease, frontotemporal dementia, and Lewy body disease.
5. Family history: Family history of psychiatric illness, treatment and response to treatment, and history of suicidal or aggressive behaviors in biological relatives are noted.
6. Personal and social history: The patient’s language preferences, life circumstances, relationships, children, employment history, cultural and societal views on psychiatric illness, stressors, trauma history, access to weapons, and legal concerns are considered. The patient's sociocultural background and its potential impact on the expression of the illness are inquired, as some beliefs may be delusional in one setting but culturally sanctioned in another and not necessarily a manifestation of psychiatric illness.  
7. Developmental history: Complications during childbirth, early development, history of trauma and abuse (including head trauma), education, and life experiences are explored.[21]

Physical Examination

Physical examination of a patient with schizophrenia poses unique challenges in meeting the patient's needs. The assessment should be performed with heightened sensitivity and awareness of the patient’s trauma history and potential anxiety, paranoia, aggression, or other psychiatric symptoms. In the physical examination of patients with schizophrenia, assessing general appearance, including hygiene and grooming, offers insights into self-care habits. Vital signs such as blood pressure and heart rate are crucial in identifying underlying health issues. A comprehensive examination covers neurological, cardiovascular, respiratory, and abdominal assessments, highlighting the importance of checking for medication side effects and coexisting conditions. A dermatological examination helps detect signs of substance use or skin infections. Assessing for metabolic syndrome is also essential, mainly due to the risks associated with certain antipsychotic medications.

Mental status examination

The Mental Status Examination (MSE) for schizophrenia varies based on symptom severity, specific manifestations, and coexisting conditions.

1. Appearance and behavior: Patients often present with disheveled or unusual attire, reflecting a lack of self-care. Behavior may range from psychomotor retardation to agitation, and patient responses can vary from being cooperative to being unpredictable, withdrawn, or hostile.
2. Psychomotor activity: There may be psychomotor agitation or retardation. Some patients may exhibit grossly disorganized or abnormal motor behavior, including catatonic behaviors, such as stupor, mutism, odd gestures, or posturing.
3. Speech: Speech patterns can be disorganized, tangential, or incoherent (word salad). Patients' speech may include neologisms (creating new words or phrases without meaning).
4. Mood and affect: Assess the degree of hopelessness. Affect can be flat, blunted, or inappropriate to the context of the conversation. Affect may be incongruent with the reported mood, such as laughing when discussing sad events.
5. Thought content: Delusions (fixed false beliefs) may be present and bizarre (extremely implausible). Thought broadcasting, thought insertion, or withdrawal may also be reported.
6. Thought process: Thought processes (inferred from the patient's speech) may be disorganized, leading to illogical connections, loose associations, or thought blocking when the patient suddenly stops speaking mid-sentence.
7. Perceptual abnormalities: Hallucinations, mainly auditory, are common but may be in any sensory modality. Patients may report hearing voices commenting on their actions or conversing with each other. It is important to assess for command hallucinations that tell the patient to engage in violent or dangerous behavior.
8. Risk: Assess current suicidality (ideas, plans, access to weapons), self-injury (ideas or behaviors), and aggressive ideas or behaviors.
9. Cognition: Cognitive deficits may affect memory, attention, and executive functions. Assess for orientation to person, place, and date.
10. Insight and judgment: Insight varies, with some patients partially aware of their condition while others lack insight completely. Judgment is often impaired, affecting the ability to make sound decisions or understand the consequences of actions.

No laboratory, psychometric, or radiologic studies currently exist for diagnosing schizophrenia.

Diagnostic criteria for schizophrenia

The 2 systems used in diagnosing schizophrenia are DSM-5-TR and ICD-10, which have slight variations. 

1. DSM-5-TR: According to the DSM-5-TR, published by the American Psychiatric Association (APA) in 2022, the following are the diagnostic criteria of schizophrenia:

Two (or more) of the following, each present for a significant portion of time during 1 month (or less if successfully treated). At least one of these must be (1), (2), or (3):

1. Delusions
2. Hallucinations
3. Disorganized speech (eg, frequent derailment or incoherence)
4. Grossly disorganized or catatonic behavior
5. Negative symptoms (ie, diminished emotional expression or avolition)

Significant functional decline in areas like work or relationships must be observed to diagnose this disorder since symptom onset. Continuous signs must persist for at least 6 months, including at least 1 month of active-phase symptoms, which might be less if treated. Symptoms can be prodromal or residual, including negative or attenuated active-phase symptoms. Schizoaffective, depressive, or bipolar disorders with psychotic features must be excluded. The symptoms should not be due to substance use, medication, or another medical condition. If a developmental disorder is present, the diagnosis additionally requires at least 1 month of prominent delusions or hallucinations.

2. ICD-10: The patient must exhibit at least one of the following for a period greater than or equal to 1 month:

• Thought echo, thought insertion or withdrawal, echo, and thought broadcasting
• Delusions of control, influence, or passivity; delusional perceptions
• Hallucinatory voices giving a running commentary on the patient or discussing the patient among themselves
• Persistent delusions that are culturally inappropriate or implausible

Or at least 2 of the following symptoms must be observed for a period greater than or equal to 1 month:

• Persistent hallucinations in any modality, when accompanied by fleeting or half-formed delusions
• Breaks or interpolations in thought resulting in incoherence, irrelevant speech, or neologisms
• Catatonic behavior
• Negative symptoms
• Significant and consistent transformation in the overall quality of behavior manifesting as loss of interest and social withdrawal [22]

Unlike the DSM-5-TR, the ICD-10 further categorizes schizophrenia based on the key presenting symptoms as either paranoid schizophrenia, hebephrenic schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, post-schizophrenic depression, residual schizophrenia, simple schizophrenia, schizophrenia, other, and schizophrenia, unspecified.  

Evaluation

Schizophrenia is primarily a clinical diagnosis and necessitates specific laboratory and radiographic investigations to exclude other potential causes. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia recommends the following investigations for an initial evaluation of a patient with schizophrenia.[21]

Hematology: A complete blood count (CBC) to check for anemia or signs of infection that mimic symptoms of schizophrenia. Absolute neutrophil count (ANC) should be obtained if considering or being treated with clozapine.

Blood chemistry panel: This includes testing electrolytes, renal function, liver function, and thyroid-stimulating hormone (TSH). Hypothyroidism can mimic psychiatric disorders, including depression and cognitive impairment.

Pregnancy test: A pregnancy test is recommended for women of childbearing age.

Electroencephalogram: An electroencephalogram (EEG) may be indicated based on the neurological examination or history to rule out a seizure disorder.

Imaging: Brain imaging, either CT or MRI (with MRI preferred), may be indicated based on the neurological examination or history.

Genetic testing: Chromosomal testing is suggested if indicated by physical examination or history, including developmental history.

Drug toxicology screen: This screen may be clinically indicated to detect substance use that could cause psychotic symptoms.

Additional tests

• Rapid plasma reagin (RPR) test is used to screen for syphilis, which can cause psychiatric symptoms.
• HIV testing may be advisable, as HIV infection can mimic psychiatric disorders.
• Electrocardiogram (ECG) is performed before initiating treatment with chlorpromazine, droperidol, iloperidone, pimozide, thioridazine, or ziprasidone, especially for patients with cardiac risk factors, elevated baseline QTc intervals, or when adding other medications that can increase QTc intervals.
• Abnormal Involuntary Movement Scale (AIMS) or Dyskinesia Identification System: The Condensed Use Scale (DISCUS) is used to assess baseline abnormal movements and is conducted every 6 to 12 months after initiating antipsychotic medication.

The American Psychiatric Association (APA) advises that the initial evaluation of a patient suspected of having a psychotic disorder should incorporate a quantitative assessment. This assessment aims to identify and evaluate the severity of symptoms and functional impairments, which could be crucial treatment targets.[21] 

Some objective quantitative rating scales that can be used in evaluation include:

• The Positive and Negative Syndrome Scale (PANSS) is used for measuring the symptom severity of patients with schizophrenia and for monitoring improvement. There are 2 versions, the PANSS-30 and the PANSS-6. The PANSS-30 is a comprehensive tool that includes 30 items, subdivided into positive symptoms, negative symptoms, and general psychopathology. The PANSS-6 is a shorter version, focusing on 6 essential items, and correlates well with the longer version.
• The Brief Psychiatric Rating Scale (BPRS) assesses the positive, negative, and affective/anxiety symptoms of individuals with psychotic disorders. It contains 18 items and is known for its usefulness in evaluating symptom changes over time.
• The World Health Organization Disability Assessment Schedule (WHODAS) is a tool designed to measure health and disability across various domains of life. It assesses the level of impairment in daily activities and participation in society, thereby providing a holistic view of a patient's functioning.

Treatment / Management

In the treatment of schizophrenia, a patient-centered treatment plan is essential, integrating nonpharmacological and pharmacological modalities to relieve symptoms and enhance patient functioning. Elements include selecting an appropriate treatment setting, managing risks, addressing barriers to adherence, and engaging the patient’s support network in recognizing early signs of relapse and how to access and use community resources. Informed consent is essential to this process and encompasses educating patients and their families about the potential benefits and risks of various treatment options.[21](A1)

Antipsychotic Medications

The APA recommends that patients with schizophrenia be treated with antipsychotic medication and observed for effectiveness and side effects.[21](A1)

Antipsychotic medications are divided into first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs). While SGAs typically have fewer extrapyramidal side effects and cause less tardive dyskinesia than FGAs, most SGAs, like olanzapine, quetiapine, clozapine, and risperidone, carry a higher risk of metabolic syndrome, especially olanzapine and clozapine.[23][24] Despite these differences, no clear preference exists between SGAs and FGAs overall, and individual efficacy varies, with clozapine potentially more effective in treatment-resistant schizophrenia and for those patients with a high risk for aggression or suicide.[21] The selection of specific treatments considers factors such as the severity of the illness, patient history of treatment response, the balance between medication efficacy and side effects, and patient preferences. Both FGA and SGA long-acting injectable (LAI) antipsychotic medications can be used to address treatment nonadherence or based on patient preference.[25](A1)

The primary goal of antipsychotic treatment is to alleviate symptoms and restore the patient’s normal functioning, followed by maintenance therapy to prevent symptom recurrence, reduce hospitalizations, and improve quality of life.[26] The initial dose of antipsychotic medication is influenced by factors such as drug formulation, patient characteristics, and history of antipsychotic use. Except for clozapine, dosages of most antipsychotics can be rapidly escalated to therapeutic levels once initial tolerance is confirmed, while also considering that it may take 2 to 4 weeks for patients to show an initial response.[21] The dose-response relationship for antipsychotics typically follows a hyperbolic pattern, reaching a plateau. Dosages above the approved range generally do not yield greater efficacy. While some evidence suggests that olanzapine may be more effective at doses up to 40 mg daily, this must be weighed against the potential for increased adverse effects.[27](A1)

Antipsychotic drugs achieve efficacy when their concentrations in the central nervous system are adequate to occupy around 70% of dopamine D₂ receptors. Clozapine and quetiapine are exceptions to this rule, showing lower D₂ receptor occupancies at their effective clinical doses.[1]

Careful medication selection and lower initial dosing should be considered in younger individuals experiencing their first episode of psychosis due to increased risks of weight gain and metabolic side effects.[21] Lower initial doses can reduce side effects and improve treatment adherence. First episodes often respond more quickly and to lower doses of medication than in subsequent episodes.[28] Based on pharmacokinetic considerations, older patients, especially those with health issues and taking multiple medications, should be started with one-quarter to one-half of the typical adult dose.[21](A1)

Determining the ideal dosage in acute antipsychotic treatment presents a challenge, as there is often a delay between the start of treatment, the initial response (usually 2 to 4 weeks), and the full therapeutic effect, which can span from 4 to 6 weeks or more.[21] Accelerating the dosage increase too quickly can affect tolerability and may give a false sense of the drug’s effectiveness. If there is not at least minimal improvement within the first 2 weeks at a therapeutic dose, it is unlikely that significant improvement will be observed after 4 to 6 weeks of treatment.[29][21](A1)

Management of Treatment-Resistant Schizophrenia

Approximately one-third of patients with schizophrenia are classified as having treatment-resistant schizophrenia, characterized by the persistent presence of symptoms despite 2 or more trials of antipsychotic medications at adequate doses and durations, with documented adherence.[30] For these patients, clozapine is the recommended treatment option, with about 40% of those with treatment-resistant schizophrenia responding.[30][31] Despite these encouraging outcomes, clozapine is underutilized in clinical practice, indicating the need for earlier consideration and integration into treatment strategies. Clozapine is also recommended for patients with schizophrenia with persistent, substantial risks of suicide or aggression despite other treatments.[21](A1)

A gradual increase in the dose of clozapine is required to reduce the likelihood of adverse effects such as seizures, orthostatic hypotension, and sedation. Effective clozapine dosages are in the range of 300 mg daily to 450 mg daily.[21] If clozapine is tolerated but ineffective, one should increase the dose to achieve a trough blood level between 350 ng/mL and 600 ng/mL.[21] Maintaining this dosage for at least 8 weeks is recommended for efficacy assessment.[21] Regular tracking of the absolute neutrophil count (ANC) is mandatory to mitigate the risk of agranulocytosis, starting with testing before the initiation of clozapine, weekly checks for the first 6 months, every 2 weeks for the next 6 months, and then monthly monitoring as long as the patient is receiving clozapine.[32] Due to the risk of agranulocytosis, all patients on clozapine are registered in the U.S. Clozapine Risk Evaluation and Mitigation Strategy (REMS) Program (www.clozapinerems.com) that tracks absolute neutrophil counts over time. Clozapine's adverse effect profile differs from other antipsychotic medications. In addition to the rare but severe risk of neutropenia, there is also an increased risk of seizure with high doses or rapid dose escalation and myocarditis.[32] Clozapine can cause gastrointestinal hypomotility, constipation with fecal impaction, ileus, and death; a prophylactic bowel regimen may be required.[33] (A1)

Sialorrhea, a common adverse effect of clozapine present in 90% of patients, can be initially managed with nonpharmacologic methods.[34] If these are ineffective, the next step is topical treatments such as ipratropium or atropine. Prompt management is essential to prevent discomfort, stigma, and aspiration pneumonia.[35](B2)

The APA recommends that patients with schizophrenia whose symptoms have improved with antipsychotic medication continue their treatment with the same medication for effective ongoing symptom management.[21] Electroconvulsive therapy can be considered in treatment-resistant cases where its efficacy rates range from 40% to 70%.[36](A1)

Psychosocial Interventions 

Besides medication, there are important evidence-based psychosocial interventions for patients with schizophrenia, including:

• Psychoeducation
• Assertive community treatment if there is a history of poor engagement with services
• Coordinated specialty care programs for people experiencing a first episode of psychosis
• Cognitive-behavioral therapy for psychosis (CBTp) 
• Supported employment services
• Supportive psychotherapy
• Social Skills Training
• Family interventions
• Cognitive remediation [21]
(A1)

Differential Diagnosis

As psychotic features are present in various other mental disorders, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th ed, Text Revision (DSM-5-TR), the differential diagnoses for schizophrenia are wide, including but not limited to:

Major depressive or bipolar disorder with psychotic or catatonic features: If hallucinations or delusions occur only during major depressive or manic episodes, the diagnosis is a depressive or bipolar disorder with psychotic features, depending on the timing and severity of mood disturbances.

Schizoaffective disorder: This diagnosis requires concurrent depressive or manic episodes with active-phase schizophrenia symptoms, with mood symptoms prevalent for most of the active phase.

Schizophreniform and brief psychotic disorder: Schizophreniform disorder is diagnosed when psychotic symptoms last less than 6 months, whereas brief psychotic disorder spans from 1 day to less than 1 month.

Delusional disorder: Distinguished from schizophrenia by the absence of other characteristic schizophrenia symptoms like pronounced hallucinations or disorganized speech.

Schizotypal personality disorder: Characterized by subthreshold schizophrenia symptoms in conjunction with persistent personality traits.

Obsessive-compulsive and body dysmorphic disorder: These disorders involve intense preoccupations with obsessions, compulsions, or body-focused concerns, differing from schizophrenia, although the obsessions can reach delusional proportions.

Posttraumatic stress disorder: PTSD includes hallucinatory flashbacks and hypervigilance that reach paranoia but is diagnosed based on experiencing a traumatic event and specific symptom patterns related to the event.

Autism spectrum and communication disorders: These disorders may include psychotic-like symptoms but are distinguished by social interaction deficits and repetitive behaviors. Schizophrenia is diagnosed concurrently only if there are significant hallucinations or delusions for at least 1 month.

Other mental disorders with psychotic episodes: Schizophrenia is diagnosed when the psychosis is persistent and not attributable to substances or other medical conditions, as can be seen in patients with delirium or substance-induced psychotic disorders.

Toxicity and Adverse Effect Management

The adverse effects of antipsychotic medications can be divided into the following categories:

Extrapyramidal Symptoms

• Tardive syndromes: Tardive dyskinesia (TD), tardive dystonia, and tardive akathisia can develop after prolonged exposure to antipsychotic medications and are characterized by involuntary movements in the lower face, limbs, and trunk. Symptoms such as grimacing, lip-smacking, tongue protrusions, and excessive blinking may become permanent even after discontinuing the medication. Compared to first-generation antipsychotic medications (FGAs), second-generation antipsychotic medications (SGAs) are thought to pose a lower risk of inducing tardive syndromes. The APA recommends treating tardive dyskinesia with a reversible inhibitor of the vesicular monoamine transporter 2 (VMAT2), such as valbenazine or deutetrabenazine.

• Parkinsonism: Antipsychotic-induced parkinsonism involves bradykinesia, tremor, rigidity, and akinesia and can be managed via a reduction in dose, changing medications, or using amantadine or an anticholinergic medication such as benztropine.

• Akathisia: The restlessness of akathisia is characterized by near-constant motion and can cause dysphoria and even suicidality. It generally develops over days to weeks of antipsychotic treatment. FGAs and aripiprazole are particularly associated with akathisia, while SGAs such as clozapine, olanzapine, and quetiapine carry lower risk. Reducing the dose of the antipsychotic medication, changing medications, adding a benzodiazepine, or adding a beta-adrenergic antagonist medication are suggestions for treating akathisia.

• Acute dystonia: This painful condition comes on suddenly and can be triggered by antipsychotic medications, causing prolonged muscle contractions manifesting as oculogyric crisis, torticollis, and laryngospasm (which can be life-threatening). FGAs appear to precipitate acute dystonia more frequently than SGAs. The APA recommends treatment with anticholinergic medication.

Neuroleptic Malignant Syndrome 

Neuroleptic malignant syndrome (NMS) is a rare but potentially lethal effect of antipsychotic medications, affecting 0.02% to 0.04% of patients with a 5% mortality rate. NMS is a medical emergency. Risk factors include the use of high-potency FGAs, rapid dose escalation, and a prior history of NMS (there may be up to a 40% recurrence rate). Symptoms include muscle rigidity, autonomic instability, altered mental status, fever, and elevated creatinine phosphokinase.[35]

Treatment involves immediately stopping all antipsychotic medications, aggressive intravenous hydration, electrolyte correction, and transfer to a higher level of care. Dantrolene and bromocriptine are used to treat moderate to severe NMS, and electroconvulsive therapy (ECT) is an option for treatment-resistant NMS.[35]

Prolactin Elevation 

High-potency FGAs and some SGAs (risperidone, paliperidone, and amisulpride) have a greater propensity to cause prolactin elevation. This is due to dopamine D₂ receptor antagonism in the anterior pituitary, leading to disruptions in the hypothalamic-pituitary-gonadal axis and symptoms such as breast enlargement, galactorrhea, sexual dysfunction, and menstrual irregularities. Management strategies include lowering the dosage of the current antipsychotic medication, switching to an antipsychotic medication with a lower risk of increasing prolactin levels, or considering the addition of bromocriptine, a dopamine agonist.[35]

If symptoms such as headache and vision changes are present in concert with elevated prolactin levels 4 times the upper limit of normal, assessment for possible pituitary tumors is warranted. 

Research indicates an association between antipsychotics that elevate prolactin levels, a decrease in bone mineral density, and a higher incidence of hip fractures.[35] Although evidence is limited, there may be a link between elevated prolactin levels and increased breast cancer risk in patients with schizophrenia.[35]

Anticholinergic Effects

Antipsychotic medications may cause anticholinergic adverse effects, including urinary retention, blurred vision, tachycardia, and constipation, as well as cognitive difficulties, especially in older patients. Decreasing the dose is the first-choice management strategy for anticholinergic adverse effects.[35]

Cardiovascular Effects

• Hyperlipidemia, especially with clozapine and olanzapine

• Myocarditis and cardiomyopathy are rare side effects of clozapine

• Orthostatic hypotension due to alpha-receptor blocking effects, especially with clozapine and quetiapine

• QTc interval prolongation, raising the risk for ventricular tachyarrhythmia (torsades de pointes)

• Tachycardia as a response to orthostatic hypotension of anticholinergic effects

Metabolic Effects

Second-generation antipsychotic medications can cause significant weight gain and hypertension and elevate lipid and glucose levels. These adverse effects raise the risk of diabetes and cardiovascular disease and contribute to adverse health outcomes. Regular monitoring for metabolic side effects is crucial. Olanzapine and clozapine carry the most significant risk for metabolic syndrome.[35]

Initial management involves lifestyle changes and structured behavioral programs. Switching to an antipsychotic with a lower metabolic risk can also help with weight loss and improve metabolic health. Symptomatic treatments include statins for dyslipidemia, antihypertensives for hypertension, and metformin for weight loss. New weight loss drugs have not been tested explicitly for antipsychotic-induced weight gain and may exacerbate gastric hypomotility. Stimulant weight loss medications are not advised due to the risk of exacerbating psychosis.[35]

Prognosis

Insidious onset, childhood or adolescent onset, poor premorbid adjustment, substance use, and cognitive impairment are indicative of a poor prognostic outcome in schizophrenia. Acute onset and living in a developed country signal comparatively better prognostic factors. Suicide is the most common cause of premature death in schizophrenia, with two-thirds of patients reporting at least one episode of suicidal ideation.[37] While positive symptoms respond to antipsychotics, there is little evidence that antipsychotics substantially improve negative or cognitive symptoms other than in situations in which these are secondary to positive symptoms.[5] With appropriate psychopharmacological and psychosocial interventions, patients with schizophrenia can have improved outcomes; however, complete recovery is only seen in 13.5% of patients.[2] The life expectancy of someone with schizophrenia is about 15 years less than the general population.[5]

Complications

Schizophrenia can lead to numerous complications. Patients often experience severe cognitive impairments, such as memory, attention, and decision-making difficulties, which can significantly affect daily functioning. Social withdrawal and isolation are common, as the struggle with social interactions leads to loneliness. There is a heightened risk of substance use disorders. Individuals with schizophrenia are also more susceptible to physical health issues like cardiovascular, metabolic, and infectious diseases. A significant complication is the increased risk of suicidal thoughts and behaviors. Maintaining employment and stable housing can be challenging due to the symptoms or frequent hospitalizations. Impaired personal care and hygiene, co-occurring mental health disorders like anxiety and depression, legal and financial problems, and the experience of stigmatization and discrimination further compound the challenges faced by those with schizophrenia. Effective management strategies, including medication, therapy, and comprehensive support services, such as housing and supportive employment, are crucial in mitigating these complications and improving overall quality of life.