Management of schizophrenia

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Schizophrenia is a psychiatric disorder (or cluster of disorders) whose symptoms include alterations in perception, thinking, mood and behavior. These include "positive symptoms" such as hallucinations and delusion and delusional thinking; negative symptoms such as a lack of motivation, apathy, poverty of speech, social withdrawal, and self-neglect; and cognitive deficits, which consist mainly of problems with short term memory, executive function and processing speed.[1] The direct effects of the disease are exacerbated by the effects of social stigma[2] and limited public understanding. This societal response can contribute to difficulty in maintaining relationships[3] and maintaining gainful employment.[4] Mortality in people with schizophrenia is 2-3 fold greater than in the general population, leading to a >10 year loss of median life expectancy.[5]

Accordingly, the ideal management of schizophrenia is multimodal and includes a mixture of psychological, pharmacological, social, educational, and employment-related interventions directed to promoting recovery, reducing the impact of the disease on quality of life, social functioning, and longevity.[6]


Hospitalization may occur with severe episodes of schizophrenia. This can be voluntary or (if mental health legislation allows it) involuntary (called civil or involuntary commitment). Long-term inpatient stays are now less common due to deinstitutionalization, although still occur.[7] Following (or in lieu of) a hospital admission, support services available can include drop-in centers, visits from members of a community mental health team or Assertive Community Treatment team, supported employment[8] and patient-led support groups. Efforts to avoid repeated hospitalization include the obtaining of community treatment orders which,following judicial approval, coerce the affected individual to receive psychiatric treatment including long-acting injections of anti-psychotic medication. This legal mechanism has been shown to increase the affected patient's time out of the hospital.[9]


Risperidone (trade name Risperdal) is a common atypical antipsychotic medication.

The mainstay of psychiatric treatment for schizophrenia is antipsychotic medication.[10] These can reduce the "positive" symptoms of psychosis. Most antipsychotics are thought to take around 7 to 14 days to have their main effect. However, these drugs fail to significantly ameliorate the negative symptoms and cognitive dysfunction.[11][12] There is evidence of clozapine, amisulpride, olanzapine and risperidone being the most effective medications, although a high proportion of studies of risperidone were undertaken by its manufacturer, Janssen-Cilag, and should be interpreted with this in mind.[13] In those on antipsychotics, continued use decreases the risk of relapse.[14][15] There is little evidence regarding consistent benefits from their use beyond two or three years.[15]

Treatment of schizophrenia changed dramatically in the mid-1950s with the development and introduction of the first antipsychotic chlorpromazine.[16] Others such as haloperidol and trifluoperazine soon followed.

It remains unclear whether the newer antipsychotics reduce the chances of developing neuroleptic malignant syndrome, a rare but serious and potentially fatal neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs.[17]

Most people on antipsychotics get side effects. People on typical antipsychotics tend to have a higher rate of extrapyramidal side effects while some atypicals are associated with considerable weight gain, diabetes and risk of metabolic syndrome; this is most pronounced with olanzapine, while risperidone and quetiapine are also associated with weight gain.[13] Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.[13] The American Psychiatric Association generally recommends that atypicals be used as first line treatment in most patients, but further states that therapy should be individually optimized for each patient.[18]

Response of symptoms to medication is variable; "Treatment-resistant schizophrenia" is the failure to respond to two or more antipsychotic medications given in therapeutic doses for six weeks or more.[19] Patients in this category may be prescribed clozapine,[20] a medication of superior effectiveness but several potentially lethal side effects including agranulocytosis and myocarditis.[21] Clozapine is the only medication proven to be more effective for persons who do not respond to other types of antipsychotics.[22] It also appears to reduce suicide in people with schizophrenia. As clozapine suppresses the development of bone marrow, in turn reducing white blood cells which can lead to infection, blood tests are taken for the first six months on this medication.[23]

Adjunctive agents in Schizophrenia[edit]

Note: Only adjuncts for which at least one double-blind randomised placebo-controlled trial has provided support are listed in this table.

Adjuncts[24][25] Symptoms against which efficacy is known Notable AEs seen in clinical trials Highest quality of clinical data available N Notes
Adjuncts to Clozapine[26][27]
Amisulpride Global Extrapyramidal side effects (e.g. tremor, dystonia, akathisia, etc.), headache, somnolence, insomnia, elevated serum prolactin, etc. 1 DB-RPCTs 16 Not approved for use in the US or Canada. Approved for use in Australia, Europe and several countries in East Asia. Can prolong the QT interval, some in vivo evidence[28] suggests it may have anti-diabetogenic effects and hence may improve metabolic parameters in patients on clozapine.
Aripiprazole Global, esp. negative Akathisia 1 DB-RPCT 61 Can also improve metabolic side effects of clozapine (including body weight). Six studies so far; only one negative.
Risperidone Global Impaired cognitive functioning, prolactin elevation and hyperglycaemia 2 DB-RPCTs, 1 DB-RCT 357 (DB-RPCTs) & 24 (DB-RCT) 11 studies have been conducted, 5 negative. A meta-analysis[26] found no clinically significant difference between risperidone augmentation and placebo augmentation.
Sulpiride Global Increased serum prolactin 1 DB-RPCT 28 Not approved for use in the US, Canada and Australia.
Ziprasidone Global QTc interval prolongation 1 DB-RCT 24 Was compared with risperidone in the one DB-RCT.
Citalopram Negative symptoms Well-tolerated 1 DB-RPCT 61 Can prolong the QT interval and since clozapine can prolong the QT interval too it's advisable to avoid their concurrent use in patients with cardiovascular risk factors.
Fluvoxamine Negative and depressive symptoms Elevated serum levels of clozapine (via inhibition of P450 cytochromes) Open-label studies NA Improved metabolic parameters
Mirtazapine Negative, depressive and cognitive symptoms Weight gain 2 DB-RPCTs (1 negative) 80 5-HT2A/2C/3 & α2 adrenoceptor antagonist
Lamotrigine Negative & depressive symptoms Stevens-Johnson syndrome, toxic epidermal necrolysis, etc. 4 DB-RPCTs (2 negative 108 Usually a relatively well-tolerated anticonvulsant, but because of risk of potentially-fatal dermatologic AEs the dose must be slowly titrated up in order to prevent these AEs. A meta-analysis[26] found that it was ineffective.
Topiramate Negative symptoms Cognitive impairment, sedation, asthenia 2 DB-RPCTs (1 negative) 57 Can cause cognitive impairment and hence should probably be avoided in patients with cognitive impairments.
Valproate Reduced anxiety & depression Weight gain, hair loss One open-label study comparing it with lithium NA Increases the expression of mGluR2 and GAD67 via histone deacetylase (HDAC) inhibition.
Glutamatergic agents[29][30]
CX-516 Global Well-tolerated 1 DB-RPCT 18 Statistically significant improvement in total symptoms but no significant improvement in negative and positive symptoms when considered separately.
Memantine Global Well-tolerated 1 DB-RPCT 21 Statistically significant improvement in negative and total symptomtology.
Lithium Global Weight gain, hypersalivation 1 DB-RPCT, 1 DB-RCT 10 (DB-RPCT), 20 (DB-RCT) Increased risk of neurological side effects such as neuroleptic malignant syndrome.
E-EPA Global (especially negative and cognitive symptoms) Well-tolerated 3 DB-RPCT (1 negative) 131 Ester of the ω-3 fatty acid, eicosapentaenoic acid.
Adjuncts to other antipsychotics
Anti-inflammatory agents[31][32]
Aspirin[33] Global (especially positive symptoms) Well-tolerated 1 DB-RPCT 70 Increased risk of bleeding, but seems relatively well-tolerated.
Celecoxib Global (especially negative symptoms) Well-tolerated 3 DB-RPCTs (1 negative) 147 May increased the risk of cardiovascular events (which is particularly worrisome as schizophrenia patients are a higher risk group for cardiovascular events). Case series (N=2) suggests efficacy in augmenting clozapine.
Minocycline[34][35][36][37] Global Well-tolerated 4 DB-RPCTs 164 Increased risk of blood dyscarsias.
ω-3 fatty acids Global Well-tolerated 6 DB-RPCTs (1 negative)[38] 362 May have protective effects against depression.
Pregnenolone[39][40][41][42] Global Well-tolerated 3 DB-RPCTs 100 Levels of this neurosteroid in the body are elevated by clozapine treatment.
D-alanine[44][45] Global Well-tolerated 1 DB-RPCT 31 A D-amino acid with affinity towards the glycine site on the NMDA receptor.
D-serine Global (especially negative symptoms) Well-tolerated 4 DB-RPCTs 183 Affinity towards the glycine site on NMDA receptors. D,Souza 2013,[46] Heresco-Levy 2005,[47] Lane 2005,[48] Lane 2010,[49] Tsai 1999,[50] Weiser 2012[51]
Glycine Global (predominantly positive symptoms) Well-tolerated 5 DB-RPCTs 219 Endogenous NMDA receptor ligand.
N-acetylcysteine[52] Global (especially negative symptoms) Well-tolerated 3 DB-RPCTs 140 Cystine and glutathione prodrug.[53][54] Cystine increases intracellular glutamate levels via the glutamate-cystine anti porter.

Berk 2008,[55] Berk 2011,[56] Carmeli 2012,[57] Lavoie 2008[58]

Sarcosine Global (especially negative symptoms) Well-tolerated 3 DB-RPCTs 112 GlyT1 antagonist (i.e. glycine reuptake inhibitor). Also known as N-methylglycine. Lane 2005,[48] Lane 2006,[59] Lane 2008,[60] Lane 2010,[49] Tsai 2004[61]
Donepezil Global Well-tolerated 6 DB-RPCTs (5 negative; or 12 DB-RPCTs if one includes cross-over trials; 8 negative in total) 378, 474 (including cross-over trials) Possesses antidepressant effects according to one trial.
Galantamine Cognition Well-tolerated 5 DB-RPCTs (1 negative) 170 Robust nootropic
Rivastigmine Cognition Well-tolerated 3 DB-RPCTs (all 3 negative; 5 trials including cross-over trials; 4 negative) 93, 131 (including cross-over trials) Seems to be a weaker nootropic
Tropisetron[65][66][67][68] Cognitive and negative symptoms Well-tolerated 3 DB-RPCTs 120 Agonist at α7 nAChRs; antagonist at 5-HT3. Expensive (>$20 AUD/tablet).
Escitalopram[70] Negative symptoms Well-tolerated 1 DB-RPCT 40 May increase risk of QT interval prolongation.
Fluoxetine Negative symptoms Well-tolerated 4 DB-RPCTs (3 negative) 136 The safest of antidepressants listed here in overdose.[71] Risk of QT interval prolongation is lower than with escitalopram (but still exists).
Mianserin[72] Negative and cognitive symptoms Well-tolerated 2 DB-RPCTs 48 Weight gain, sedation, dry mouth, constipation and dizziness. Blood dyscarsias are a possible adverse effect and both the Australian Medicines Handbook and British National Formulary 65 (BNF 65) recommend regular complete blood counts to be taken.[73][74]
Mirtazapine[72] Cognition,[75][76] negative and positive symptoms†[77] Well-tolerated ≥4 DB-RPCTs (one negative) 127 Relatively safe in overdose. Produces significant sedation and weight gain, however, which could potentially add to the adverse effects of atypical antipsychotics. Can reduce antipsychotic-induced akathisia.[78]
Ritanserin Negative symptoms Well-tolerated 2 DB-RPCTs 73 5-HT2A/2C antagonist. Not clinically available.
Trazodone Negative symptoms Well-tolerated 2 DB-RPCTs 72 5-HT2A antagonist and SSRI. Has sedative effects and hence might exacerbate some of the side effects of atypical antipsychotics.
Alpha-lipoic acid[79][80] Weight gain Well-tolerated 1 DB-RPCT 360 Offset antipsychotic drug-induced weight gain. Increased total antioxidant status. May also increase GSH:GSSH (reduced glutathione:oxidized glutathione) ratio.[81]
L-Theanine[82][83][84] Positive, activation, and anxiety symptoms Well-tolerated 2 DB-RPCTs 40 Glutamic acid analog. Primary study noted reduction in positive, activation, and anxiety symptoms. Additional studies have noted improvements in attention.[85][86][87][88] Research suggests that theanime has a regulatory effect on the nicotine acetylcholine receptor-dopamine reward pathway, and was shown to reduced dopamine production in the midbrain of mice.[89]
Famotidine[90] Global Well-tolerated 1 DB-RPCT 30 May reduce the absorption of vitamin B12 from the stomach. Might also increase susceptibility to food poisoning.
Ginkgo biloba Tardive dyskinesia, positive symptoms Well-tolerated 4 DB-RPCTs 157 Atmaca 2005,[91] Doruk 2008,[92] Zhang 2001,[93] Zhang 2001,[94] Zhang 2006,[95] Zhang 2011,[96] Zhou 1999[97]
Ondansetron[98] Negative and cognitive symptoms Well-tolerated 3 DB-RPCTs 151 5-HT3 antagonist. May prolong the QT interval. Expensive (>$4 AUD/tablet).
SAM-e[99] Aggression Well-tolerated 1 DB-RPCT 18 Study noted improvement of aggressive behavior and quality of life impairment.
Vitamin C[100][101][102][103] Global Well-tolerated 1 DB-RPCT 40 Improves BPRS scores.

Acronyms used:
DB-RPCT — Double-blind randomised placebo-controlled trial.
DB-RCT — Double-blind randomised controlled trial.
AE — Adverse effect.

Note: Global in the context of schizophrenia symptoms here refers to all four symptom clusters.

N refers to the total sample sizes (including placebo groups) of DB-RCTs.

† No secondary sources could be found on the utility of the drug in question, treating the symptom in question (or any symptom in the case of where † has been placed next to the drug's name).

Nicotine patch[edit]

Following an observation that tobacco smoking eases effects of schizophrenia, the nicotine patch has been proposed as a treatment for schizophrenia.[unreliable medical source?] [104]


Psychotherapy is also widely recommended, though not widely used in the treatment of schizophrenia, due to reimbursement problems or lack of training. As a result, treatment is often confined to psychiatric medication.[105]

Cognitive behavioral therapy (CBT) is used to target specific symptoms and improve related issues such as self-esteem and social functioning. Although the results of early trials were inconclusive [106] as the therapy advanced from its initial applications in the mid-1990s, meta-analytic reviews suggested CBT to be an effective treatment for the psychotic symptoms of schizophrenia.[107][108] Nonetheless more recent meta analyses have cast doubt upon the utility of CBT as a treatment for the symptoms of psychosis[109][110][111]

Another approach is cognitive remediation therapy, a technique aimed at remediating the neurocognitive deficits sometimes present in schizophrenia. Based on techniques of neuropsychological rehabilitation, early evidence has shown it to be cognitively effective, resulting in the improvement of previous deficits in psychomotor speed, verbal memory, nonverbal memory, and executive function, such improvements being related to measurable changes in brain activation as measured by fMRI.[112]

Metacognitive training: In view of a many empirical findings [113] suggesting deficits of metacognition (thinking about one’s thinking, reflecting upon one’s cognitive process) in patients with schizophrenia, metacognitive training (MCT) [113][114] is increasingly adopted as a complementary treatment approach. MCT aims at sharpening the awareness of patients for a variety of cognitive biases (e.g. jumping to conclusions, attributional biases, over-confidence in errors), which are implicated in the formation and maintenance of schizophrenia positive symptoms (especially delusions),[115] and to ultimately replace these biases with functional cognitive strategies.

The training consists of 8 modules and can be obtained cost-free from the internet in 15 languages.[113][114] Studies confirm the feasibility [116] and lend preliminary support to the efficacy [113][117][118] of the intervention. Recently, an individualized format has been developed which combines the metacognitive approach with methods derived from cognitive-behavioral therapy.[119]

Family Therapy or Education, which addresses the whole family system of an individual with a diagnosis of schizophrenia, has been consistently found to be beneficial, at least if the duration of intervention is longer-term.[120][121][122] Aside from therapy, the impact of schizophrenia on families and the burden on careers has been recognized, with the increasing availability of self-help books on the subject.[123][124] There is also some evidence for benefits from social skills training, although there have also been significant negative findings.[125][126] Some studies have explored the possible benefits of music therapy and other creative therapies.[127][128][129]

The Soteria model is alternative to inpatient hospitalization using full non professional care and a minimal medication approach.[130] Although evidence is limited, a review found the programme equally as effective as treatment with medications but due to the limited evidence did not recommend it as a standard treatment.[131] Training in the detection of suble facial expressions has been used to improve facial emotional recognition.[132]


Transcranial Magnetic Stimulation (TMS) appears to be effecting in alleviating the negative symptoms and cognitive deficits see in schizophrenia, a recent double-blind randomized sham controlled study of deep-TMS add-on treatment noted an 8 point reduction in the Scale for the Assessment of Negative Symptoms (SANS) in patients.[133][134][135][136][137][138][139][140][141]

Electroconvulsive therapy is not considered a first line treatment but may be prescribed in cases where other treatments have failed. It is more effective where symptoms of catatonia are present,[142] and is recommended for use under NICE guidelines in the UK for catatonia if previously effective, though there is no recommendation for use for schizophrenia otherwise.[143] Psychosurgery has now become a rare procedure and is not a recommended treatment for schizophrenia.[144]

Omega-3 fatty acids[edit]

An unconventional approach is the use of omega-3 fatty acids, with one study finding some benefits from their use as a dietary supplement.[145]

A 2003 review of four randomized controlled trials of EPA (an omega-3 fatty acid) vs. placebo as adjunctive treatment for schizophrenia found that two of the trials detected a significant improvement on positive and negative symptoms, and suggested that EPA may be an effective adjunct to antipsychotics.[146] The most recent meta-analysis (2006) failed however to find a significant effect.[147] A 2007 review found that studies of omega-3 fatty acids in schizophrenia, despite being mostly of high quality, have produced inconsistent results and small effect sizes of doubtful clinical significance.[148]


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