Derived from the Greek 'schizo' (splitting) and 'phren' (mind) with the term first coined by Eugen Bleuler in 1908, schizophrenia is a functional psychotic disorder characterized by the presence of delusional beliefs, hallucinations, and disturbances in thought, perception, and behavior. Traditionally, symptoms have divided into two main categories: positive symptoms which include hallucinations, delusions, and formal thought disorders, and negative symptoms such as anhedonia, poverty of speech, and lack of motivation. The diagnosis of schizophrenia is clinical; made exclusively after obtaining a full psychiatric history and excluding other causes of psychosis. Risk factors include birthing complications, the season of birth, severe maternal malnutrition, maternal influenza in pregnancy, family history, childhood trauma, social isolation, cannabis use, minority ethnicity, and urbanization. Due to its relative complexity and heterogeneity, the etiology and pathophysiological mechanisms are not fully understood. Despite a low prevalence, schizophrenia's global burden of disease is immense. Over half of the patients have significant co-morbidities, both psychiatric and medical, making it one of the leading causes of disability worldwide. The diagnosis correlates with a 20% reduction in life expectancy, with up to 40% of deaths attributed to suicide.
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 play 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:
The incidence is also up to ten times greater in children of African and Caribbean migrants compared to Caucasians according to a study conducted in Britain. 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 use of the drug and risk of developing schizophrenia.
Though the prevalence of the disease varies globally, estimates are that schizophrenia affects approximately 1% of adults, whereas prevalence in the US is 0.6% to 1.9% . 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. 
There are three main hypotheses regarding the development of schizophrenia. The neurochemical abnormality hypothesis argues that an imbalance of dopamine, serotonin, glutamate, and GABA result 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 insinuate the potential role of glutaminergic hypoactivity while serotonergic hyperactivity has also been shown to play a role in schizophrenia development.
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 frontal lobes and hippocampus are also seen, potentially contributing to a range of cognitive and memory impairments associated with the disease.
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:
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:
Or, at least two of the following symptoms must be observed, for a period greater than or equal to a month:
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:
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.
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:
For the initial treatment of acute psychosis, it is recommended to commence 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 antipsychotic (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 24 weeks and then monthly 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. 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 schizophrenia patients which can exacerbate both positive and negative symptoms, therefore both 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.
As psychotic features can manifest in various other mental disorders, there are wide-ranging differentials for schizophrenia, including but not limited to:
Antipsychotic side effects subdivide into five categories.
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. However, SGAs have far fewer extrapyramidal side effects than their FGA counterparts, therefore may be preferentially used.
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.
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 schizophrenia patients respond poorly to antipsychotics, and around 7% show no response. Clozapine is the therapeutic option in such instances.
A significant percentage of schizophrenia patients die from cardiovascular disease. Educating patients on the importance of modifying risk factors such as increasing exercise, healthier diets, and smoking cessation will decrease their risk of cardiovascular problems and reduce the mortality rate. Moreover, cognitive behavioral therapy has been shown to improve patient compliance and decrease future hospital admissions.
Alongside educating patients about the importance of making healthy lifestyle choices, it is also imperative that the physicians, nurses and other allied health professionals work together in diligently monitoring patients while admitted. Patients on clozapine need to have their WBC measured regularly as they are at risk of agranulocytosis while a risk assessment should be carried out on all new patients to evaluate their risk of harm to self or others. Outside of the hospital setting, community psychiatric nurses and family physicians can also educate the patient and provide further information, while also monitoring for early signs of relapse.
|||Messias EL,Chen CY,Eaton WW, Epidemiology of schizophrenia: review of findings and myths. The Psychiatric clinics of North America. 2007 Sep; [PubMed PMID: 17720026]|
|||Davis J,Eyre H,Jacka FN,Dodd S,Dean O,McEwen S,Debnath M,McGrath J,Maes M,Amminger P,McGorry PD,Pantelis C,Berk M, A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neuroscience and biobehavioral reviews. 2016 Jun; [PubMed PMID: 27073049]|
|||Chong HY,Teoh SL,Wu DB,Kotirum S,Chiou CF,Chaiyakunapruk N, Global economic burden of schizophrenia: a systematic review. Neuropsychiatric disease and treatment. 2016 [PubMed PMID: 26937191]|
|||De Luca V,Tharmalingam S,Müller DJ,Wong G,de Bartolomeis A,Kennedy JL, Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia. Brain research. 2006 Jun 30 [PubMed PMID: 16725119]|
|||Patel KR,Cherian J,Gohil K,Atkinson D, Schizophrenia: overview and treatment options. P [PubMed PMID: 25210417]|
|||Kirkbride JB,Errazuriz A,Croudace TJ,Morgan C,Jackson D,Boydell J,Murray RM,Jones PB, Incidence of schizophrenia and other psychoses in England, 1950-2009: a systematic review and meta-analyses. PloS one. 2012; [PubMed PMID: 22457710]|
|||Jablensky A, The diagnostic concept of schizophrenia: its history, evolution, and future prospects. Dialogues in clinical neuroscience. 2010; [PubMed PMID: 20954425]|
|||Gründer G,Heinze M,Cordes J,Mühlbauer B,Juckel G,Schulz C,Rüther E,Timm J, Effects of first-generation antipsychotics versus second-generation antipsychotics on quality of life in schizophrenia: a double-blind, randomised study. The lancet. Psychiatry. 2016 Aug [PubMed PMID: 27265548]|
|||Ventriglio A,Gentile A,Bonfitto I,Stella E,Mari M,Steardo L,Bellomo A, Suicide in the Early Stage of Schizophrenia. Frontiers in psychiatry. 2016 [PubMed PMID: 27445872]|
|||Auquier P,Lançon C,Rouillon F,Lader M, Mortality in schizophrenia. Pharmacoepidemiology and drug safety. 2007 Dec; [PubMed PMID: 17944000]|