사용자:Yjs5497/연습장/항정신병제제

위키백과, 우리 모두의 백과사전.
2세대 항정신병제제 중 하나인 올란자핀

항정신병제제 또는 신경안정제는 정신병의 치료에 이용하는 정신 약물군 중 하나이다. 정신병에는 망상, 환각, 사고 장애 및 조현병, 양극성 장애 등이 있으며, 이러한 제제는 정신병이 아닌 질환의 치료에도 쓰인다. (ATC 코드 N05 참조) [1]

정형적 항정신병제제로 알려져 있는 1세대 항정신병제제는 1950년대에 개발되었다. 2세대 항정신병제제인 비정형적 항정신병제제가 더 최근에 개발되었지만, 이 쪽이 항정신병제제의 대부분을 차지한다. 항정신병제제는 뇌의 도파민 경로의 수용체를 차단하는 경향이 있고, 2세대 항정신병제제는 세로토닌 수용체에도 반응하게 개발된 경우가 있다.

이 제제의 부작용으로 잘 알려진 것은 1세대의 경우 비정상적 운동을 일으키는 추체외로 증상 및 고프로락틴혈증이며, 2세대에서는 체중 증가 및 대사장애이다.[2] 약을 줄여가면서 나타날 수 있는 일시적인 금단 증상으로는 불면증, 불안, 정신증 및 운동 장애가 있고, 이러한 것들 때문에 환자 및 그 보호자들이 기저 증상이 재발했다고 오해할 소지가 있다. [3][4]

용도[편집]

항정신병제는 다음과 같은 질환에 처방된다.

항정신병제제를 치매나 불면증 환자에게 처방하는 것은 다른 치료제로 치료가 불가능한 경우를 제외하면 권장되지 않는다.[15] 또한 정신증이 있는 어린이를 제외하고는 아동에 항정신병제제를 투여하는 것,[15] 2가지 이상의 다른 항정신병제제를 동일한 사람에게 처방하는 것은 보통 권장되지 않는다. [15]

조현병[편집]

대조군의 24%에 비교해 항정신병제제를 투여한 41%가 치료반응을 보이기는 하지만, 시간이 지나면서 항정신병제제에 대한 치료 반응은 떨어져 왔으며, 항정신병제제에 대한 논문은 이 약물군에 대한 사용을 지지하는 쪽으로 편향되어 있을 가능성이 잠재적으로 존재한다.[16] 광범위하게 사용되는 비정형적 항정신병제제인 리스페리돈의 경우, 위약군과 대조해 볼 때 그 효과는 미미하다.[17]

개발도상국에서 조현병으로 진단받은 사람들의 장기간 예후가 선진국보다 더 좋았다는 세계 보건 기구의 논문 두 개가 팔표된 이후로, 어떤 사람들은 항정신병제제에 대한 장기간 예후에 대한 의문을 제기했다. 왜냐하면 개발도상국의 환자들은 선진국의 환자들보다 항정신병제제에 대한 접근성이 낮으며, 더 비공식적인 치료를 받고 지역보건의 자원에 더 의존적이기 때문이다.[18][19]

Some argue that the evidence for antipsychotics from discontinuation-relapse studies may be flawed, because they do not take into account that antipsychotics may sensitize the brain and provoke psychosis if discontinued, which may then be wrongly interpreted as a relapse of the original condition. Evidence from comparison studies indicates that at least some individuals with schizophrenia recover from psychosis without taking antipsychotics, and may do better in the long term than those that do take antipsychotics. Some argue that, overall, the evidence suggests that antipsychotics only help if they are used selectively and are gradually withdrawn as soon as possible[20] and have referred to the "Myth of the antipsychotic".[21]

어떤 사람들은 항정신병제제가 뇌를 감작시켜서 정신증의 증상을 감작시켰을수도 있고, 약을 중단했을 때 정신증을 다시 드러내기 때문에, 이를 질환이 재발했다고 오해할 수도 있다는 점을 들어 항정신병제제의 중단-재발 연구에 허점이 있을 수 있다고 주장한다. [4] 대조 연구 자료에서 도출된 자료는 최소한 항정신병제제를 복용하지 않은 환자가 약을 복용한 환자보다 장기간의 예후를 볼 때는 더 잘 회복되는 Case도 있기는 하다는 것을 나타낸다. [22]

The methods used in trials of antipsychotics, despite stating that the overall quality is "rather good," reported issues with the selection of participants (including that in schizophrenia trials up to 90% of people who are generally suitable do not meet the elaborate inclusion and exclusion criteria, and that negative symptoms have not been properly assessed despite companies marketing the newer antipsychotics for these); issues with the design of trials (including pharmaceutical company funding of most of them, and inadequate experimental "blinding" so that trial participants could sometimes tell whether they were on placebo or not); and issues with the assessment of outcomes (including the use of a minimal reduction in scores to show "response," lack of assessment of quality of life or recovery, a high rate of discontinuation, selective highlighting of favorable results in the abstracts of publications, and poor reporting of side-effects).[23]

While flupenthixol an injectable form of antipsychotic which is given every few weeks is extensively used there is little evidence to support this use.[24] There is little long term data on the benefits of antipsychotics (beyond two to three years).[25] It is recommended that if a person is without symptoms for a year stopping the use of antipsychotics be considered.[25]

Bipolar disorder[편집]

Antipsychotics are routinely used, often in conjunction with mood stabilisers such as lithium/valproate, as a first-line treatment for manic and mixed episodes associated with bipolar disorder.[14][26] The reason for this combination is the therapeutic delay of the aforementioned mood stabilisers (for valproate therapeutic effects are usually seen around five days after treatment is commenced whereas lithium usually takes at least a week[26] before the full therapeutic effects are seen) and the comparatively rapid antimanic effects of antipsychotic drugs.[27] The antipsychotics have a documented efficacy when used alone in acute mania/mixed episodes.[5]

Three atypical antipsychotics (lurasidone,[12] olanzapine[11] and quetiapine[8]) have also been found to possess efficacy in the treatment of bipolar depression as a monotherapy. Whereas only olanzapine[28] and quetiapine[29][30] have been proven to be effective broad-spectrum (i.e. against all three types of relapse— manic, mixed and depressive) prophylactic (or maintenance) treatments in patients with bipolar disorder. A recent Cochrane review also found that olanzapine had a less favourable risk/benefit ratio than lithium as a maintenance treatment for bipolar disorder.[31]

The American Psychiatric Association and the UK National Institute for Health and Clinical Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes.[32][33] They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of "compliance" or "adherence" with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalization.

Dementia[편집]

Antipsychotics in old age dementia showed a modest benefit compared to placebo in managing aggression or psychosis, but this is combined with a significant increase in serious adverse events. Thus antipsychotics should not be used routinely to treat dementia with aggression or psychosis, but may be an option in a few cases where there is severe distress or risk of physical harm to others.[34] Psychosocial interventions may reduce the need for antipsychotics.[35]

Unipolar Depression[편집]

A number of second-generation (or atypical) antipsychotics have proven to be effective adjuncts in the treatment of major depressive disorder[36][37] of which aripiprazole, quetiapine and olanzapine (when used in conjunction with fluoxetine) have received FDA labelling for this indication.[9] Quetiapine has also proven effective as a monotherapy in major depressive disorder.[38]

Other[편집]

Besides the above uses antipsychotics may be used for Obsessive-compulsive disorder, Posttraumatic stress disorder, personality disorders, Tourette syndrome, autism (for which both aripiprazole and risperidone are FDA-labelled) and agitation in those with dementia.[39] Evidence however does not support the use of atypical antipsychotics in eating disorders or personality disorder.[40] Risperidone may be useful for obsessive compulsive disorder.[39] The use of low doses of antipsychotics for insomnia, while common, is not recommended as there is little evidence of benefit and concerns regarding adverse effects.[40][41] Low dose antipsychotics may also be used in treatment of impulse-behavioural and cognitive-perceptual symptoms of borderline personality disorder.[42]

In children they may be used in those with disruptive behavior disorders, mood disorders and pervasive developmental disorders or intellectual disability.[43] Antipsychotics are only weakly recommended for Tourette syndrome as well they are effective side effects are common.[44] The situation is similar in autism spectrum disorder.[45] Much of the evidence for the off-label use of antipsychotics (for example, for dementia, OCD, PTSD, Personality Disorders, Tourette's) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems.[46] A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.[47] A survey of children with pervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly for irritability, aggression, and agitation. Recently, risperidone was approved by the US FDA for the treatment of irritability in children and adolescents with autism.[48]

Aggressive challenging behavior in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomized controlled trial, however, found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.[49]

Typicals versus atypicals[편집]

While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy and reduced side effects than typical medications this may not be true.[50][51] One review concluded there were no differences[52] while another[53] found that atypicals were "only moderately more efficacious".[52] These conclusions were, however, questioned by another review, which found that clozapine, amisulpride, and olanzapine and risperidone were more effective[52][54] Clozapine has appeared to be more effective than other atypical antipsychotics,[52][55] although it has previously been banned due to its potentially lethal side effects. While controlled clinical trials of atypicals reported that extrapyramidal symptoms occurred in 5–15% of patients, a study of bipolar disorder in a real world clinical setting found a rate of 63%, questioning the generalizability of the trials.[56] Due to bias in the research the accuracy of comparisons of atypical antipsychotics is a concern.[57]

In 2005 the US government body National Institute of Mental Health published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project).[58] This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 44 파운드 (20 kg) over 18 months) and increases in glucose, cholesterol, and triglycerides. The mean and maximal doses used for olanzapine were considerably higher than standard practice, and this has been postulated as a biasing factor that may explain olanzapine's superior efficacy over the other atypical antipsychotics studied, where doses were more in line with clinically relevant practices.[59] No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine, although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%).[60]

Compliance has not been shown to be different between the two types.[61]

Many researchers question the first-line prescribing of atypicals over typicals, and some even question the distinction between the two classes.[62][63][64] In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and EPS틀:Expand acronym with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter.[59][65] The UK government organization NICE recently revised its recommendation favoring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient's preferences.

The re-evaluation of the evidence has not necessarily slowed the bias towards prescribing the atypicals.[66]

Adverse effects[편집]

Antipsychotics are associated with a range of side effects. It is well-recognized that many people stop taking them (around two-thirds even in controlled drug trials) due in part to adverse effects.[67]

Common (≥1% and up to 50% incidence for most antipsychotic drugs) adverse effects of antipsychotics include
  • Sedation (particularly common in patients on clozapine, olanzapine, quetiapine, chlorpromazine and zotepine[68])
  • Headaches
  • Dizziness
  • Diarrhoea
  • Anxiety
  • Extrapyramidal side effects (particularly common in patients on first-generation antipsychotics) which includes:
- Akathisia — an often distressing sense of inner restlessness.
- Dystonia
- Parkinsonism
- Tremor
  • Hyperprolactinaemia (rare for those on clozapine, quetiapine and aripiprazole[14][68]) which can cause:
- Galactorrhoea — unusual secretion of breast milk.
- Gynaecomastia
- Sexual dysfunction (in both sexes)
- Osteoporosis
  • Orthostatic hypotension
  • Weight gain (particularly prominent in patients on clozapine, olanzapine, quetiapine and zotepine[68])
  • Anticholinergic side effects such as:
- Amnesia (although this is not a common adverse effect in patients on antipsychotics)
- Angle-closure glaucoma (also rare in patients on antipsychotics)
- Blurred vision
- Constipation
- Dry mouth (although hypersalivation may also occur)
- Reduced perspiration
  • Tardive dyskinesia appears to be more frequent in those on high-potency first-generation antipsychotics such as haloperidol and tends to appear after chronic and not acute treatment.[69] It is characterised by slow (hence the tardive) repetitive, involuntary and purposeless movements, most often of the face, lips, legs or torso which tend to resist treatment and are frequently irreversible. The rate of appearance of TD is about 5% per year of use of antipsychotic drug (whatever the drug used).
Rare/Uncommon (<1% incidence for most antipsychotic drugs) adverse effects of antipsychotics include
  • Blood dyscarias (e.g. agranulocytosis, leukopaenia and neutropaenia) which is more common in patients on clozapine.
  • Metabolic syndrome and other metabolic problems such as Type II diabetes mellitus — particularly common with clozapine, olanzapine and zotepine. In American studies African Americans appeared to be at a heightened risk for developing type II diabetes mellitus.[70] Evidence suggests that females are more sensitive to the metabolic side effects of first-generation antipsychotic drugs than males.[71] Metabolic adverse effects appears to be mediated by the following mechanisms:
- Blocking the M3 muscarinic acetylcholine receptor which is responsible for regulating the release of insulin.[72]
- Inappropriately changing the body's energy source from carbohydrates to lipids.[73]
- Causing weight gain by antagonising the histamine H1 and serotonin 5-HT2Creceptors[74] and perhaps by interacting with other neurochemical pathways in the central nervous system.[75]
- Autonomic instability which can manifest itself with tachycardia, nausea, vomiting, diaphoresis, etc.
- Hyperthermia — elevated body temperature.
- Mental status change (confusion, hallucinations, coma, etc.)
- Muscle rigidity
- Laboratory abnormalities (e.g. elevated creatinine kinase, reduced iron plasma levels, electrolyte abnormalities, etc.)

Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.[78][79] Antipsychotics may also increase the risk of early death in individuals with dementia.[80] In individuals without psychosis, doses of antipsychotics can produce the "negative symptoms" of schizophrenia such as amotivation.[81] Antipsychotics typically worsen symptoms in people who suffer from depersonalisation disorder.[82] Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is said to be a common practice but not necessarily evidence-based or recommended, and there have been initiatives to curtail it.[83] Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.[84]

Other[편집]

Chronic treatment with antipsychotics may reduce amounts of brain tissue and potentially cause some of the symptoms believed to be due to schizophrenia[85] According to studies in macaque monkeys cell loss only affects the number of glial cells and not the numbers of neuronal cells.[86] Continuous use of neuroleptics has been shown to decrease the total brain volume by 10% in macaque monkeys.[87][88] The effects may differ for typical versus atypical antipsychotics and may interact with different stages of disorders.[89] Such effects were not clearly tested for by pharmaceutical companies prior to obtaining approval for placing the drugs on the market.[90][91]

A minor loss of brain tissue has been reported in schizophrenics treated with antipsychotics.[92] Brain volume was negatively correlated with both duration of illness and antipsychotic dosage. No association was found with severity of illness or abuse of other substances. An accompanying editorial said: "The findings should not be construed as an indication for discontinuing the use of antipsychotic medications as a treatment for schizophrenia. But they do highlight the need to closely monitor the benefits and adverse effects of these medications in individual patients, to prescribe the minimal amount needed to achieve the therapeutic goal [and] to consider the addition of nonpharmacological approaches that may improve outcomes."[92][93]

Withdrawal[편집]

Withdrawal symptoms from antipsychotics may emerge during dosage reduction and discontinuation. Withdrawal symptoms can include nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. The psychological withdrawal symptoms can include psychosis, and can be mistaken for a relapse of the underlying disorder. Conversely, the withdrawal syndrome may also be a trigger for relapse. Better management of the withdrawal syndrome may improve the ability of individuals to discontinue antipsychotics.[3][4]

Tardive dyskinesia may abate during withdrawal from the antispsychotic agent, or it may persist.[94] Withdrawal-related psychosis from antipsychotics is called "supersensitivity psychosis", and is attributed to increased number and sensitivity of brain dopamine receptors, due to blockade of dopaminergic receptors by the antipsychotics,[95] which often leads to exacerbated symptoms in the absence of neuroleptic medication.[96] Efficacy of antipsychotics may likewise be reduced over time, due to this development of drug tolerance.[4]

Withdrawal effects may also occur when switching a person from one antipsychotic to another, (presumably due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects.[97] The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[98] The process of cross-titration involves gradually increasing the dose of the new medication while gradually decreasing the dose of the old medication.[69]

참조 문헌[편집]

  1. ↑ Cubeddu, Richard Finkel, Michelle A. Clark, Luigi X. (2009). 《Pharmacology》 4판. Philadelphia: Lippincott Williams & Wilkins. 151쪽. ISBN 9780781771559. 
  2. ↑ Frankenburg FR, Dunayevich E, Albucher RC, Talavera F. Schizophrenia. 2013 Aug 22 [cited 2013 Oct 2]; Available from: http://emedicine.medscape.com/article/288259-overview
  3. ↑ 가 나 Dilsaver SC, Alessi NE (1988년 3월). “Antipsychotic withdrawal symptoms: phenomenology and pathophysiology”. 《Acta Psychiatr Scand》 77 (3): 241–6. doi:10.1111/j.1600-0447.1988.tb05116.x. PMID 2899377. 
  4. ↑ 가 나 다 라 Moncrieff J (2006). “Why is it so difficult to stop psychiatric drug treatment? It may be nothing to do with the original problem”. 《Med. Hypotheses》 67 (3): 517–23. doi:10.1016/j.mehy.2006.03.009. PMID 16632226.  인용 오류: 잘못된 <ref> 태그; "Moncrieff-2006"이 다른 콘텐츠로 여러 번 정의되었습니다
  5. ↑ 가 나 Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009년 1월). “Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis”. 《Lancet》 373 (9657): 31–41. doi:10.1016/S0140-6736(08)61764-X. PMID 19058842. 
  6. ↑ Goikolea JM, Colom F, Torres I, Capapey J, Valentí M, Undurraga J, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. Journal of Affective Disorders [Internet]. 2013 Jan 25 [cited 2013 Oct 2];144(3):191–8. Available from: http://www.sciencedirect.com/science/article/pii/S0165032712005691
  7. ↑ Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010 Feb;71(2):150–62.
  8. ↑ 가 나 Thase ME. Quetiapine monotherapy for bipolar depression. Neuropsychiatr Dis Treat [Internet]. 2008 Feb [cited 2013 Oct 2];4(1):21–31. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515925/
  9. ↑ 가 나 Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Oct 2]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  10. ↑ Suppes T, Datto C, Minkwitz M, Nordenhem A, Walker C, Darko D. Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. Journal of Affective Disorders [Internet]. 2010 Feb [cited 2013 Oct 2];121(1–2):106–15. Available from: http://www.sciencedirect.com/science/article/pii/S0165032709004674
  11. ↑ 가 나 Tohen M, Katagiri H, Fujikoshi S, Kanba S. Efficacy of olanzapine monotherapy in acute bipolar depression: A pooled analysis of controlled studies. Journal of Affective Disorders [Internet]. 2013 Jul [cited 2013 Oct 2];149(1–3):196–201. Available from: http://www.sciencedirect.com/science/article/pii/S0165032713000773
  12. ↑ 가 나 Lowes R. Lurasidone Approved for Bipolar Depression [Internet]. Medscape. 2013 [cited 2013 Oct 2]. Available from: http://www.medscape.com/viewarticle/807204
  13. ↑ Fruyt JD, Deschepper E, Audenaert K, Constant E, Floris M, Pitchot W, et al. Second generation antipsychotics in the treatment of bipolar depression: a systematic review and meta-analysis. J Psychopharmacol [Internet]. 2012 May 1 [cited 2013 Oct 2];26(5):603–17. Available from: http://jop.sagepub.com/content/26/5/603
  14. ↑ 가 나 다 라 Taylor D, Paton C, Kapur S, Taylor D. The Maudsley prescribing guidelines in psychiatry. Chichester, West Sussex: John Wiley & Sons; 2012.
  15. ↑ 가 나 다 “American Psychiatric Association Five Things Physicians and Patients Should Question”. 《Choosing Wisely》. 2013년 9월 23일에 확인함. 
  16. ↑ Leucht S, Arbter D, Engel RR, Kissling W, Davis JM (2009년 4월). “How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials”. 《Mol. Psychiatry》 14 (4): 429–47. doi:10.1038/sj.mp.4002136. PMID 18180760. 
  17. ↑ Rattehalli RD, Jayaram MB, Smith M (2010). Rattehalli, Ranganath, 편집. “Risperidone versus placebo for schizophrenia”. 《Cochrane Database of Systematic Reviews》 (1): CD006918. doi:10.1002/14651858.CD006918. PMID 20091611. 
  18. ↑ Jablensky A, Sartorius N, Ernberg G; 외. (1992). “Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study”. 《Psychol Med Monogr Suppl》 20: 1–97. doi:10.1017/S0264180100000904. PMID 1565705. 
  19. ↑ Hopper K, Wanderling J (2000). “Revisiting the developed versus developing country distinction in course and outcome in schizophrenia: results from ISoS, the WHO collaborative followup project. International Study of Schizophrenia”. 《Schizophr Bull》 26 (4): 835–46. doi:10.1093/oxfordjournals.schbul.a033498. PMID 11087016. 
  20. ↑ Whitaker R (2004). “The case against antipsychotic drugs: a 50-year record of doing more harm than good”. 《Med. Hypotheses》 62 (1): 5–13. doi:10.1016/S0306-9877(03)00293-7. PMID 14728997. 
  21. ↑ James, Adam (2008년 3월 2일). “Myth of the antipsychotic”. 《The Guardian》. Guardian News and Media Limited. 2012년 7월 27일에 확인함. 
  22. ↑ Harrow M, Jobe TH (2007년 5월). “Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications: a 15-year multifollow-up study”. 《J. Nerv. Ment. Dis.》 195 (5): 406–14. doi:10.1097/01.nmd.0000253783.32338.6e (년 이후로 접속 불가 2013-07-28). PMID 17502806. 
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  90. ↑ DeLisi LE (2008년 3월). “The Concept of Progressive Brain Change in Schizophrenia: Implications for Understanding Schizophrenia”. 《Schizophrenia Bulletin》 34 (2): 312–21. doi:10.1093/schbul/sbm164. PMC 2632405. PMID 18263882. 
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  93. ↑ Lewis DA (2011년 2월). “Antipsychotic medications and brain volume: do we have cause for concern?”. 《Arch. Gen. Psychiatry》 68 (2): 126–7. doi:10.1001/archgenpsychiatry.2010.187. PMID 21300942. 
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  96. ↑ Gitlin M, Nuechterlein K, Subotnik KL; 외. (2001년 11월). “Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia”. 《Am J Psychiatry》 158 (11): 1835–42. doi:10.1176/appi.ajp.158.11.1835. PMID 11691689. 
  97. ↑ Lambert TJ (2007). “Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes”. 《J Clin Psychiatry》. 68 Suppl 6: 10–3. PMID 17650054. 
  98. ↑ Group, BMJ, 편집. (2009년 3월). 〈4.2.1〉. 《British National Formulary》 57판. United Kingdom: Royal Pharmaceutical Society of Great Britain. 192쪽. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse. 
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