Schizophrenia

Etiology

Several studies postulate that the development of schizophrenia results from abnormalities in multiple neurotransmitters, such as dopaminergic, serotonergic, and alpha-adrenergic hyperactivity or glutaminergic and GABA hypoactivity. Genetics also plays a fundamental role - there is a 46% concordance rate in monozygotic twins and a 40% risk of developing schizophrenia if both parents are affected. The gene neuregulin (NGR1), which is involved in glutamate signaling and brain development, has been implicated, alongside dysbindin (DTNBP1), which helps glutamate release, and catecholamine O-methyl transferase (COMT) polymorphism, which regulates dopamine function.

As aforementioned, there are also several environmental factors associated with an enhanced risk of developing the disease:

• Abnormal fetal development and low birth weight
• Gestational diabetes
• Preeclampsia
• Emergency cesarean section and other birthing complications
• Maternal malnutrition and vitamin D deficiency
• Winter births - associated with a 10% higher relative risk
• Urban residence - increases the risk of developing schizophrenia by 2 to 4%

The incidence is also up to ten times greater in children of African and Caribbean migrants compared to whites, according to a study conducted in Britain.[1] The association between cannabis use and psychosis has been widely studied, with recent longitudinal studies suggesting a 40% increased risk, while also suggesting a dose-effect relationship between the use of the drug and the risk of developing schizophrenia.[2]

Epidemiology

Though the prevalence of the disease varies globally, estimates are that schizophrenia affects approximately 1% of adults, whereas prevalence in the United States is 0.6 to 1.9% [5]. Men are slightly more likely to be diagnosed and have an earlier onset than women, while African-Caribbean migrants and their descendants also have a higher incidence.[6]

Pathophysiology

There are three main hypotheses regarding the development of schizophrenia. The neurochemical abnormality hypothesis argues that an imbalance of dopamine, serotonin, glutamate, and GABA results in the psychiatric manifestations of the disease. It postulates that four main dopaminergic pathways are involved in the development of schizophrenia. This dopamine hypothesis attributes the positive symptoms of the illness to excessive activation of D2 receptors via the mesolimbic pathway, while low levels of dopamine in the nigrostriatal pathway are theorized to cause motor symptoms through their effect on the extrapyramidal system. Low mesocortical dopamine levels resulting from the mesocortical pathway are thought to elicit the negative symptoms of the disease. Other symptoms such as amenorrhea and decreased libido may be caused by elevated prolactin levels due to decreased availability of tuberoinfundibular dopamine as a result of blockage of the tuberoinfundibular pathway. Evidence showing exacerbation of positive and negative symptoms in schizophrenia by NMDA receptor antagonists insinuates the potential role of glutaminergic hypoactivity while serotonergic hyperactivity has also been shown to play a role in schizophrenia development.[5] 

There are also arguments that schizophrenia is a neurodevelopmental disorder based on abnormalities present in the cerebral structure, an absence of gliosis suggesting in utero changes, and the observation that motor and cognitive impairments in patients precede the illness onset.

Conversely, the disconnect hypothesis focuses on the neuroanatomical changes seen in PET and fMRI scans. There is a reduction in grey matter volume in schizophrenia, present not only in the temporal lobe but in the parietal lobes as well. Differences in the frontal lobes and hippocampus are also seen, potentially contributing to a range of cognitive and memory impairments associated with the disease. 

History and Physical

There are slight variations in the diagnostic criteria of schizophrenia depending on the classification system used.

Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) 

Two or more of the following symptoms must be present for a significant portion of time during a one-month period:

• Delusions
• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behavior
• Negative symptoms. 

There must also be social/occupational dysfunction, while signs of disturbance must persist for at least six months, including at least one month of symptoms.

International Classification of Diseases (ICD-10)

The patient must exhibit at least one of the following, for a period greater than or equal to a month:

• Thought insertion, echo, broadcast, or withdrawal
• Delusions of control, influence, or passivity
• Hallucinatory voices providing a running commentary of the patient
• Persistent delusions that are culturally inappropriate or implausible

Or, at least two of the following symptoms must be observed, for a period greater than or equal to a month[7]:

• Persistent hallucinations in any modality when accompanied by fleeting delusions
• Breaks of interpolations in thought resulting in incoherence or neologisms
• Catatonic behavior
• Negative symptoms
• Significant and consistent transformation in the overall quality of behavior manifesting as anhedonia and social withdrawal

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

 In addition to asking about these symptoms, it is also important to elicit:

1. Past medical history, drug history, and family history
2. Social history, including the use of recreational drugs and alcohol
3. Any recent neurological impairments such as altered consciousness or memory problems, head injury, stroke, seizures, faints, dizzy spells, visual impairment, marked tremor, or muscle stiffness
4. Potential organic causes of psychosis such as Parkinson's disease, multiple sclerosis, syphilis, AIDS, brain lesions, heavy metal toxicity, delirium, metabolic/endocrine disorders, and dementias including Alzheimer's disease, frontotemporal dementia, and Lewy body dementias

A thorough risk assessment must also be undertaken to determine the risk of harm to self and others. The first schizophrenic episode usually occurs during early adulthood or late adolescence. Individuals often lack insight at this stage; therefore, few will present directly to seek help for their psychotic symptoms. Common presentations include a relative noticing social withdrawal, personality changes, or uncharacteristic behavior; deliberate self-harm or suicide attempts; calling the police to report their delusional symptoms, or referral via the criminal justice system. The use of screening tools such as COPS (Criteria of Prodromal Syndromes), SIPS (Structured Interview for Prodromal Syndromes), and PACE (Personal Assessment and Crisis Evaluation Clinic) has been shown to increase the detection rate of schizophrenia in premorbid states although there is controversy surrounding indicating treatment at this stage.

Evaluation

After conducting a full psychiatric history, it is imperative to conduct a thorough systems review and a mental state examination where appearance, behavior, mood, speech, cognition, and insight need to be assessed, alongside determining evidence of perceptual delusions or formal thought disorders. Though schizophrenia is primarily a clinical diagnosis, specific laboratory and radiographic investigations are useful to exclude other potential causes:

• Urea and electrolytes - an electrolyte imbalance can cause delirium
• Serum calcium - hypoparathyroidism or hyperparathyroidism can, on occasion, have psychiatric manifestations
• Blood glucose - hypoglycemia can produce confusion which can be mistaken for psychosis
• Thyroid function tests - depression is associated with hypothyroidism and may present with psychotic features - severe hyperthyroidism also correlates with changes in mental state
• 24-hour cortisol collection - both hypercortisolism (Cushing syndrome) and adrenocortical insufficiency (Addison disease) can present with psychiatric symptoms
• 24 hour catecholamine/5-HIAA collection - in cases of suspected phaeochromocytoma/carcinoid syndrome
• Urinary toxicology screen - detection of recreational drugs such as cannabis
• CT head/MRI - in cases of significant neurological impairment or suspected neurological abnormality
• HIV/syphilis serology - both infections can cause psychiatric symptoms

Treatment / Management

For the initial treatment of acute psychosis, it is recommended to start an oral second-generation antipsychotic (SGA) such as aripiprazole, olanzapine, risperidone, quetiapine, asenapine, lurasidone, sertindole, ziprasidone, brexpiprazole, molindone, iloperidone, etc. Sometimes, if clinically needed, alongside a benzodiazepine such as diazepam, clonazepam, or lorazepam to control behavioral disturbances and non-acute anxiety. First-generation antipsychotics (FGA) like trifluoperazine, fluphenazine, haloperidol, pimozide, sulpiride, flupentixol, chlorpromazine, etc., are not commonly used as the first line but can be used.

Once the acute phase is controlled, switching to a depot preparation like aripiprazole, paliperidone, zuclopenthixol, fluphenazine, haloperidol, pipotiazine, or risperidone is recommended as it increases medication adherence and compliance, improving outcomes and decreasing relapses.

Cognitive behavioral therapy (CBT) and the use of art and drama therapies help counteract the negative symptoms of the disease, improve insight, and assist relapse prevention.

Clozapine is used in case of treatment resistance - if there has been a poor response to at least two different antipsychotics, and require initial weekly blood tests for six months, biweekly for six months, and then every four weeks to monitor white blood cell count due to the risk of agranulocytosis.

Other options in treatment resistance include combining antipsychotics, adding lamotrigine, mirtazapine, donepezil, D-alanine, D-serine, estradiol, memantine, or allopurinol to an antipsychotic. The role of electroconvulsive therapy (ECT) is limited but has been used.

During the maintenance phase, prophylaxis and rehabilitation back into the community are vital priorities - and establishing the minimum necessary effective dose of antipsychotics should also take place during this period. Post-schizophrenic depression occurs in up to 30% of patients: if a dysphoric mood is evident, consider reducing the antipsychotic dose, treating with antidepressants or anxiolytics, or switching to a second-generation antipsychotic. There is significant substance abuse amongst patients with schizophrenia which can exacerbate both positive and negative symptoms; therefore, psychosocial and pharma therapeutic approaches should be used to treat the misuse. Clozapine may be given in patients with extensive, persisting substance misuse. 

The treatment of those identified as at risk of developing a psychotic disorder is controversial. Treatment of co-existing disorders and with individual CBT and family intervention is advocated, although no long-term evidence exists regarding its efficacy in preventing a psychotic episode or reducing its severity.

Differential Diagnosis

As psychotic features can manifest in various other mental disorders, there are wide-ranging differentials for schizophrenia, including but not limited to:

• Substance-induced psychotic disorder
• Mood disorders with psychotic features
• Sleep-related disorders
• Delusional disorder
• Paranoid personality disorder
• Schizotypal personality disorder
• Pervasive developmental disorder
• Psychosis secondary to organic causes

Toxicity and Adverse Effect Management

Antipsychotic side effects subdivide into five categories.

Extrapyramidal

• Tardive dyskinesia: though symptoms are irreversible, vitamin E has been shown to prevent further deterioration
• Parkinsonism: bradykinesia, tremors, and rigidity can occur a week after administration - can be managed via a reduction in dose or the use of an antimuscarinic such as oral benztropine 
• Akathisia: can occur after a month of antipsychotic use and treated using propranolol and benzodiazepines
• Acute dystonia: managed via a parenteral muscarinic such as benztropine administered intravenously or intramuscularly 

Anticholinergic

• Dry mouth; urinary retention; blurred vision; glaucoma; constipation

Anti-adrenergic

• Sexual dysfunction; tachycardia; postural hypotension

Antihistaminic

• Weight gain, sedation; All patients should be advised to increase their physical activity and monitor their dietary intake.

Idiosyncratic

• Altered glucose tolerance, skin photosensitivity, cholestatic jaundice, hypersensitivity reactions, yellow pigmentation of the skin, neuroleptic malignant syndrome; The neuroleptic malignant syndrome may be fatal and is characterized by increasing rigidity, pyrexia, and fluctuating consciousness - the patient should receive immediate medical care.

Recent efficacy studies such as Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and European First-Episode Schizophrenia Trials (EUFEST) found no significant difference between the first-generation antipsychotics such as haloperidol and newer second-generation antipsychotics such as olanzapine and risperidone.[8] However, SGAs have far fewer extrapyramidal side effects than their FGA counterparts; therefore, they may be preferentially used.

Prognosis

In schizophrenia, the prognosis is dependent on several factors. Insidious onset, childhood or adolescent onset, poor premorbid adjustment, and cognitive impairment are indicative of a poor prognostic outcome, whereas acute onset, female sex, and living in a developed country signal comparatively better prognostic factors. However, suicide is the most common cause of premature death in schizophrenia, with two-thirds of patients reporting at least one episode of suicidal ideation.[9]

Complications

Treatment-resistant schizophrenia is when the condition fails to respond to at least two antipsychotic medications for at least six weeks; up to 30% of patients with schizophrenia respond poorly to antipsychotics, and around 7% show no response. Clozapine is the therapeutic option in such instances.