Management of schizophrenia

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Management of schizophrenia
Specialtypsychiatry

Management of schizophrenia usually involved many aspects including psychological, pharmacological, social, educational, and employment-related interventions directed to recovery, reducing the impact of the disease on quality of life, social functioning, and longevity.[1]

Hospitalization[edit]

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.[2] 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[3] 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.[4]

Medication[edit]

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

The mainstay of psychiatric treatment for schizophrenia is antipsychotic medication.[5] Medication might improve a number of outcomes found to be important to patients, including positive, acute and psychotic symptoms, and social and vocational functioning.[6] Medication 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.[7][8] 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.[9] In those on antipsychotics, continued use decreases the risk of relapse.[10][11] There is little evidence regarding consistent benefits from their use beyond two or three years.[11]

Treatment of schizophrenia changed dramatically in the mid-1950s with the development and introduction of the first antipsychotic chlorpromazine.[12] 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.[13]

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.[9] Risperidone has a similar rate of extrapyramidal symptoms to haloperidol.[9] 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.[14]

The 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.[15] Patients in this category may be prescribed clozapine, a medication that may be more effective at reducing symptoms of schizophrenia, but treatment may come with a higher risk of several potentially lethal side effects including agranulocytosis and myocarditis.[16][17] Clozapine is the only medication proven to be more effective for people who do not respond to other types of antipsychotics.[18] 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.[19] The risk of experiencing agranulocytosis due to clozapine treatment is higher in elderly people, children, and adolescents.[16] The effectiveness in the studies also needs to be interpreted with caution as the studies may have an increased risk of bias.[16]

Add on agents[edit]

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

Adjuncts[20][21] Symptoms against which efficacy is known Notable adverse effects seen in clinical trials Highest quality of clinical data available N Notes
Adjuncts to clozapine[22][23]
Antipsychotics
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[24] 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[22] 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.
Antidepressants
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
Anticonvulsants
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[22] 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[25][26]
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.
Other
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[27][28]
Aspirin[29] 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[30][31][32][33] Global Well-tolerated 4 DB-RPCTs 164 Increased risk of blood dyscarsias.
ω-3 fatty acids Global Well-tolerated 6 DB-RPCTs (1 negative)[34] 362 May have protective effects against depression.
Pregnenolone[35][36][37][38] Global Well-tolerated 3 DB-RPCTs 100 Levels of this neurosteroid in the body are elevated by clozapine treatment.
Glutamatergics[25][39]
D-alanine[40][41] 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,[42] Heresco-Levy 2005,[43] Lane 2005,[44] Lane 2010,[45] Tsai 1999,[46] Weiser 2012[47]
Glycine Global (predominantly positive symptoms) Well-tolerated 5 DB-RPCTs 219 Endogenous NMDA receptor ligand.
N-acetylcysteine[48] Global (especially negative symptoms) Well-tolerated 3 DB-RPCTs 140 Cystine and glutathione prodrug.[49][50] Cystine increases intracellular glutamate levels via the glutamate-cystine anti porter.

Berk 2008,[51] Berk 2011,[52] Carmeli 2012,[53] Lavoie 2008[54]

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,[44] Lane 2006,[55] Lane 2008,[56] Lane 2010,[45] Tsai 2004[57]
Cholinergics[58][59][60]
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[61][62][63][64] Cognitive and negative symptoms Well-tolerated 3 DB-RPCTs 120 Agonist at α7 nAChRs; antagonist at 5-HT3. Expensive (>$20 AUD/tablet).
Antidepressants[65]
Escitalopram[66] 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.[67] Risk of QT interval prolongation is lower than with escitalopram (but still exists).
Mianserin[68] 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.[69][70]
Mirtazapine[68] Cognition,[71][72] negative and positive symptoms†[73] 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.[74]
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.
Other
Alpha-lipoic acid[75][76] Weight gain Well-tolerated 1 DB-RPCT 360 Offset antipsychotic drug-induced weight gain. Increased total antioxidant status. May also increase GSH:GSSG (reduced glutathione:oxidized glutathione) ratio.[77]
L-Theanine[78][79][80] 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.[81][82][83][84] 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.[85]
Famotidine[86] 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,[87] Doruk 2008,[88] Zhang 2001,[89] Zhang 2001,[90] Zhang 2006,[91] Zhang 2011,[92] Zhou 1999[93]
Ondansetron[94] Negative and cognitive symptoms Well-tolerated 3 DB-RPCTs 151 5-HT3 antagonist. May prolong the QT interval. Expensive (>$4 AUD/tablet).
SAM-e[95] Aggression Well-tolerated 1 DB-RPCT 18 Study noted improvement of aggressive behavior and quality of life impairment. while in another study SAM-e has been purported to have a contributory effect on psychosis [96]
Vitamin C[97][98][99][100] Global Well-tolerated 1 DB-RPCT 40 Improves BPRS scores.

Acronyms used:
DB-RPCT — Double-blind randomized placebo-controlled trial.
DB-RCT — Double-blind randomized controlled trial.

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).

Psychosocial[edit]

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.[101]

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[102] 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.[103][104] Nonetheless, more recent meta analyses have cast doubt upon the utility of CBT as a treatment for the symptoms of psychosis[105][106][107]

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.[108]

Metacognitive training: In view of many empirical findings [109] suggesting deficits of metacognition (thinking about one's thinking, reflecting upon one's cognitive process) in patients with schizophrenia, metacognitive training (MCT) [109][110] 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),[111] 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.[109][110] Studies confirm the feasibility [112] and lend preliminary support to the efficacy [109][113][114] of the intervention. Recently, an individualized format has been developed which combines the metacognitive approach with methods derived from cognitive-behavioral therapy.[115]

Family Therapy or Education, which addresses the whole family system of an individual with a diagnosis of schizophrenia, may be beneficial, at least if the duration of intervention is longer-term.[116][117][118] A 2010 Cochrane review concluded that many of the clinical trials that studied the effectiveness of family interventions were poorly designed, and may over estimate the effectiveness of the therapy. High-quality randomized controlled trials in this area are required.[118] 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.[119][120] There is also some evidence for benefits from social skills training, although there have also been significant negative findings.[121][122] Some studies have explored the possible benefits of music therapy and other creative therapies.[123][124][125]

The Soteria model is alternative to inpatient hospitalization using full non professional care and a minimal medication approach.[126] 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.[127] Training in the detection of subtle facial expressions has been used to improve facial emotional recognition.[128]

Diet[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.[129]

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.[130] The most recent meta-analysis (2006) failed however to find a significant effect.[131] 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.[132] Individualized nutrition interventions and supplementation has been proposed as an adjunct to pharmacological therapy in people with schizophrenia, though this approach has not been evaluated in clinical trials to determine the efficacy of such an approach in improving symptoms.[133]

Other[edit]

Various brain stimulation techniques have been used to treat the positive symptoms of schizophrenia, in particular auditory verbal hallucinations (AVHs), and investigations are ongoing.[134] Most studies focus on transcranial direct-current stimulation (tDCM), and repetitive transcranial magnetic stimulation (rTMS).[135] Transcranial magnetic stimulation is low-cost, noninvasive, and almost free of side-effects making it a good therapeutic choice with promising outcomes.[134] Low-frequency TMS of the left temperoparietal cortex (the region containing Broca's area) can reduce auditory hallucinations.[134] rTMS seems to be the most effective treatment for those with persistent AVHs, as an add-on therapy.[135] AVHs are not resolved in up to 30 per cent of those on antipsychotics and a further percentage still experience only a partial response.[135] Techniques based on focused ultrasound for deep brain stimulation could provide insight for the treatment of AVHs.[135]

An established brain stimulation treatment is electroconvulsive therapy. This 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,[136] 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.[137] Psychosurgery has now become a rare procedure and is not a recommended treatment for schizophrenia.[138]

A study in 2014 conducted by an Australian researcher indicated that the pericarp powder of Garcinia mangostana L. have the ability to reduce oxidative stress as an effective treatment for schizophrenia by increasing glutathione S-transferase levels which enhances mitochondrial activity over a period of 180 days under a sustained intake of 1000 mg/day.[139][140]

There may be some benefit in trying several treatment modalities at the same time, especially those that could be classed as lifestyle interventions.[141]

Peer support in which people with experiential knowledge of mental illness provide knowledge, experience, emotional, social or practical help to each other is considered an important aspect of coping with schizophrenia and other serious mental health conditions. A 2019 Cochrane reviews of evidence for peer-support interventions compared to supportive or psychosocial interventions were unable to support or refute the effectiveness of peer-support due to limited data.[142]

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