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meds:antipsychotics:home [on May 18, 2020]
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psychdb [Length of Treatment]
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 {{INLINETOC}} {{INLINETOC}}
 ===== Primer ===== ===== Primer =====
-**Antipsychotics** (also known as neuroleptics or major tranquilizers) are a class of medication ​mainly used in the treatment of psychosis in [[psychosis:​schizophrenia-scz|schizophrenia]] and psychosis/​mania in [[mood:​bipolar-i|bipolar disorder]]. Its use has expanded to neurodevelopmental,​ neurodegenerative,​ and neuropsychiatric disorders in recent years.+**Antipsychotics** (also known as **neuroleptics** or **major tranquilizers**) are a class of medications ​mainly used in the treatment of psychosis in [[psychosis:​schizophrenia-scz|schizophrenia]] and psychosis/​mania in [[bipolar:​bipolar-i|bipolar disorder]]. Its use has expanded to neurodevelopmental,​ neurodegenerative,​ and neuropsychiatric disorders in recent years.
  
-== History == +==== History ​==== 
-The first antipsychotic [[meds:​antipsychotics:​first-gen-typical:​5-chlorpromazine|chlorpromazine]] was introduced in 1955 by French psychiatrists Pierre Deniker and Jean Delay. Since then, antipsychotics have been the cornerstone treatment for psychotic disorders. Its role and scope has expanded in the treatment of other medical and psychiatric illnesses since then.+  ​* ​The first antipsychotic [[meds:​antipsychotics:​first-gen-typical:​5-chlorpromazine|chlorpromazine]] was introduced in 1955 by French psychiatrists Pierre Deniker and Jean Delay. Since then, antipsychotics have been the cornerstone treatment for psychotic ​disorders, and considered the single greatest advance in the treatment of mental ​disorders. 
 +  * Its role and scope has expanded in the treatment of other medical and psychiatric illnesses since then.
  
-===== Mechanism of Action ===== +===== The Dopamine Hypothesis ​===== 
-==== The Dopamine Hypothesis ==== +<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​ 
-<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​See also: **[[psychosis:​schizophrenia-scz|]]**</​alert>​+See also: **[[psychosis:​schizophrenia-scz|]]** 
 +</​alert>​
  
 One theory in the pathophysiology of schizophrenia is that increased dopamine activity causes the positive symptoms of schizophrenia. Similar to how methamphetamine and cocaine also increases dopamine activity, and can cause schizophrenia-like symptoms. Therefore, antipsychotics target the mesolimbic pathway to decrease the incidence of positive symptoms. Antipsychotics work by binding to dopaminergic neuroreceptors. It is important to keep in mind that this is a //​theoretical//​ model, and that the pathophysiology of schizophrenia remains poorly understood. One theory in the pathophysiology of schizophrenia is that increased dopamine activity causes the positive symptoms of schizophrenia. Similar to how methamphetamine and cocaine also increases dopamine activity, and can cause schizophrenia-like symptoms. Therefore, antipsychotics target the mesolimbic pathway to decrease the incidence of positive symptoms. Antipsychotics work by binding to dopaminergic neuroreceptors. It is important to keep in mind that this is a //​theoretical//​ model, and that the pathophysiology of schizophrenia remains poorly understood.
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 There are **4** key dopaminergic pathways that antipsychotics affect (See also: [[https://​psychopharmacologyinstitute.com/​antipsychotics-videos/​dopamine-pathways-antipsychotics-pharmacology/​|The Four Dopamine Pathways Relevant to Antipsychotics Pharmacology]]). There are **4** key dopaminergic pathways that antipsychotics affect (See also: [[https://​psychopharmacologyinstitute.com/​antipsychotics-videos/​dopamine-pathways-antipsychotics-pharmacology/​|The Four Dopamine Pathways Relevant to Antipsychotics Pharmacology]]).
  
-<​imgcaption Figure1|>​{{:​meds:​antipsychotics:​dopaminergic_pathways_of_the_brain_vertical_v3.png?​direct|The four key dopaminergic pathways of the brain}}</​imgcaption>​+<​imgcaption Figure1|>​{{:​meds:​antipsychotics:​dopaminergic_pathways_of_the_brain_vertical_v3.png?​direct&1000|The four key dopaminergic pathways of the brain}}</​imgcaption>​
  
 <panel title="​The Four Key Dopamine Pathways"​ type="​info"​ no-body="​true">​ <panel title="​The Four Key Dopamine Pathways"​ type="​info"​ no-body="​true">​
-^ Pathways ​                    ​^ Projection ​                                                                                      ​^ Relevance ​                                                                                                                                                                                                                                                                                                   +<​mobiletable 1> 
-^ Mesocortical ​        | Ventral tegmental area -> prefrontal cortex ​                                                     | Decreased dopamine leads to negative symptoms (amotivation,​ flat affect, anhedonia) ​                                                                                                                                                                                                                           +^ Pathways ​            ​^ Projection ​                                                                                               ^ Relevance ​                                                                                                                                                                                                                                                                                                                                                                              ​
-^ Mesolimbic (reward) ​ | Ventral tegmental area -> nucleus accumbens and olfactory tubercle. ​                             | Increased dopamine leading to positive symptoms (hallucinations,​ paranoia, delusions). Importantly,​ the mesolimbic pathway is the same pathway for nicotine-reward pathway. ​                                                                                                                                   +^ Mesocortical ​        | Ventral tegmental area -> prefrontal cortex ​                                                              ​| Decreased dopamine leads to negative symptoms (amotivation,​ flat affect, anhedonia). Cognitive symptoms are also thought to be due to a hypoactive mesocoritcal pathway. ​                                                                                                                                                                                                               ​
-^ Nigrostriatal ​       | Substantia nigra -> striatum (caudate and putamen) ​                                              ​| This pathway also gets blocked by antipsychotics,​ leading to [[meds:​antipsychotics:​eps|extrapyramidal symptoms (EPS)]], such as tremors, slurred speech, dystonia, and other abnormal movements. Akathisia is another side effect. ​                                                                                                        ​|+^ Mesolimbic (reward) ​ | Ventral tegmental area -> nucleus accumbens and olfactory tubercle. ​                                      ​| Increased dopamine leading to positive symptoms (hallucinations,​ paranoia, delusions). Importantly,​ the mesolimbic pathway is the same pathway for nicotine-reward pathway. ​                                                                                                                                                                                                            ​
 +^ Nigrostriatal ​       | Substantia nigra -> striatum (caudate and putamen) ​                                                       | This pathway also gets blocked by antipsychotics,​ leading to [[meds:​antipsychotics:​eps|extrapyramidal symptoms (EPS)]], such as tremors, slurred speech, dystonia, and other abnormal movements. Akathisia is another side effect. ​                                                                                                                                                     |
 ^ Tuberoinfundibular ​  | Entirely in hypothalamus,​ from arcuate (infundibular) and periventricular nuclei to the median eminence. ​ | The decrease of dopamine in this pathway, through the use of antipsychotics,​ can cause an increase prolactin ([[meds:​antipsychotics:​hyperprolactinemia|hyperprolactinemia]]),​ leading to side effects like gynecomastia,​ galactorrhea,​ and menstrual irregularities. The regular role of dopamine release in the tuberoinfundibular pathway is to tonically inhibit prolactin release. ​ | ^ Tuberoinfundibular ​  | Entirely in hypothalamus,​ from arcuate (infundibular) and periventricular nuclei to the median eminence. ​ | The decrease of dopamine in this pathway, through the use of antipsychotics,​ can cause an increase prolactin ([[meds:​antipsychotics:​hyperprolactinemia|hyperprolactinemia]]),​ leading to side effects like gynecomastia,​ galactorrhea,​ and menstrual irregularities. The regular role of dopamine release in the tuberoinfundibular pathway is to tonically inhibit prolactin release. ​ |
-</​panel>​+</​mobiletable>​</​panel>​
  
 +===== Mechanism of Action =====
 ==== Receptor Occupancy ==== ==== Receptor Occupancy ====
-The therapeutic action of an antipsychotic occurs when 65% to 85% of brain dopamine (D2) receptors are occupied.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​2892477|Farde,​ L., & Wiesel, M. D. (1988). with Antipsychotic Drugs. Arch Gen Psychiatry, 45, 71-76.]])] When more than 80% of the dopamine (D2) receptors are occupied, hyperprolactinemia and parkinsonism can result. In addition to percentage occupancy, the duration of time that the antipsychotic drug stays attached to the D2 receptor impacts the degree of [[meds:​antipsychotics:​eps|extrapyramidal symptoms (EPS)]]. For example, haloperidol remains attached to the D2 receptor //in vitro// for over 38 minutes. Atypicals like [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|clozapine]] and [[meds:​antipsychotics:​second-gen-atypical:​6-quetiapine|quetiapine]] dissociate from the D2 receptor quickly, in about 15 seconds (this has been referred to as "kiss and run"​).[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC1408069/​|Kapur,​ S., & Seeman, P. (2000). Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. Journal of Psychiatry and Neuroscience,​ 25(2), 161.]])][(Schatzberg,​ AF, Nemeroff, C . The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed. American Psychiatric Publishing, 2009.)] As a result, these rapidly dissociating atypical antipsychotics have a lower incidence of EPS. Of note, the serum level of antipsychotics do not correlate with brain occupancy due to the blood brain barrier.+The therapeutic action of an antipsychotic occurs when 65% to 85% of brain dopamine (D2) receptors are occupied.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​2892477|Farde,​ L., & Wiesel, M. D. (1988). with Antipsychotic Drugs. Arch Gen Psychiatry, 45, 71-76.]])] When more than 80% of the dopamine (D2) receptors are occupied, ​[[meds:​antipsychotics:​hyperprolactinemia|hyperprolactinemia]] ​and [[meds:​antipsychotics:​eps|parkinsonism]] can result. In addition to percentage occupancy, the duration of time that the antipsychotic drug stays attached to the D2 receptor impacts the degree of [[meds:​antipsychotics:​eps|extrapyramidal symptoms (EPS)]]. For example, haloperidol remains attached to the D2 receptor //in vitro// for over 38 minutes. Atypicals like [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|clozapine]] and [[meds:​antipsychotics:​second-gen-atypical:​6-quetiapine|quetiapine]] dissociate from the D2 receptor quickly, in about 15 seconds (this has been referred to the "kiss and run" ​hypothesis).[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC1408069/​|Kapur,​ S., & Seeman, P. (2000). Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. Journal of Psychiatry and Neuroscience,​ 25(2), 161.]])][(Schatzberg,​ AF, Nemeroff, C . The American Psychiatric Publishing Textbook of Psychopharmacology. 4th ed. American Psychiatric Publishing, 2009.)] As a result, these rapidly dissociating atypical antipsychotics have a lower incidence of EPS. Of note, the serum level of antipsychotics do not correlate with brain occupancy due to the blood brain barrier.
  
 ==== Potency ==== ==== Potency ====
- 
 <WRAP group> <WRAP group>
 <WRAP half column> <WRAP half column>
-Antipsychotic function can best be understood by their degree of affinity for the dopamine receptor, or potency (i.e. - "how much of the drug you need to produce a clinical effect?"​).[([[https://​www.biomedcentral.com/​1471-244x/​9/​24/​table/​t1|Table 1: Antipsychotic equivalent doses and Defined Daily Doses of common antipsychotics.]])][([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC2693495/​pdf/​1471-244X-9-24.pdf|Kroken,​ Rune A et al. Treatment of Schizophrenia with Antipsychotics in Norwegian Emergency Wards, a Cross-Sectional National Study. BMC Psychiatry 9 (2009): 24.]])] This can be seen in the actual dose of the antipsychotic itself (e.g. - the therapeutic dose of risperidone (high potency) is 2-3 mg, whereas quetiapine (low potency) can be up to 800 mg).+Antipsychotic function can best be understood by their degree of affinity for the dopamine receptor, or potency (i.e. - "how much of the drug you need to produce a clinical effect?"​).[([[https://​www.biomedcentral.com/​1471-244x/​9/​24/​table/​t1|Table 1: Antipsychotic equivalent doses and Defined Daily Doses of common antipsychotics.]])][([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC2693495/​pdf/​1471-244X-9-24.pdf|Kroken,​ Rune A et al. Treatment of Schizophrenia with Antipsychotics in Norwegian Emergency Wards, a Cross-Sectional National Study. BMC Psychiatry 9 (2009): 24.]])] This can be seen in the actual dose of the antipsychotic itself (e.g. - the therapeutic dose of risperidone (high potency) is 2-3 mg, whereas quetiapine (low potency) can be up to 800 mg). The potency of an antipsychotic in particular can tell you its particular effects and side effects. For example, all low potency antipsychotics (regardless if it is an FGA or SGA) have a lower incidence of EPS. This is because all low potency antipsychotics are also more anticholinergic (i.e. - in addition to targeting the D2 receptor, they also have greater anti-muscarinic activity). This means low potency antipsychotics have "​built-in"​ benztropine (an anticholinergic medication used in the treatment of EPS). Understanding the [[meds:​antipsychotics:​eps|pathophysiology of EPS]] will also help one understand why benztropine is given, and why EPS occurs with high potency antipsychotics.
  
   * **High potency** (i.e. - you only need to prescribe a "low dose" to get a clinical effect)   * **High potency** (i.e. - you only need to prescribe a "low dose" to get a clinical effect)
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 <panel type="​info"​ title="​Antipsychotic Potency Table" footer="​High potency antipsychotics have a higher risk for extrapyramidal symptoms (EPS) and hyperprolactinemia. Low potency antipsychotics have more anticholingeric symptoms and are more sedating. Typical antipsychotics have a higher propensity to cause EPS, where as atypicals are more likely to cause metabolic syndrome."​ no-body="​true">​ <panel type="​info"​ title="​Antipsychotic Potency Table" footer="​High potency antipsychotics have a higher risk for extrapyramidal symptoms (EPS) and hyperprolactinemia. Low potency antipsychotics have more anticholingeric symptoms and are more sedating. Typical antipsychotics have a higher propensity to cause EPS, where as atypicals are more likely to cause metabolic syndrome."​ no-body="​true">​
- +<​mobiletable 1> 
-^ Potency ​    ^ First Generation (Typical) ​ ^ Second Generation (Atypical) ​ ^+^ Potency ​    ​^ ​[[meds:​antipsychotics:​first-gen-typical:​home|First Generation (Typical)]]  ​^ ​[[meds:​antipsychotics:​second-gen-atypical:​home|Second Generation (Atypical)]]  ^
 | **HIGH** ​   | Haloperidol ​                | Risperidone ​                  | | **HIGH** ​   | Haloperidol ​                | Risperidone ​                  |
 |             | Flupenthixol ​               | Paliperidone ​                 | |             | Flupenthixol ​               | Paliperidone ​                 |
 |             | Fluphenazine ​               |                               | |             | Fluphenazine ​               |                               |
 |             | Pimozide ​                   |                               | |             | Pimozide ​                   |                               |
-|             ​| ​                            ​| ​                              | 
 | **MEDIUM** ​ | Loxapine ​                   | Olanzapine ​                   | | **MEDIUM** ​ | Loxapine ​                   | Olanzapine ​                   |
 |             | Zuclopenthixol ​             | Ziprasidone ​                  | |             | Zuclopenthixol ​             | Ziprasidone ​                  |
 |             | Perphenazine ​               | Aripiprazole ​                 | |             | Perphenazine ​               | Aripiprazole ​                 |
-|             ​| ​                            ​| ​                              | 
 | **LOW** ​    | Chlorpromazine ​             | Quetiapine ​                   | | **LOW** ​    | Chlorpromazine ​             | Quetiapine ​                   |
 |             | Methotrimeprazine ​          | Clozapine ​                    | |             | Methotrimeprazine ​          | Clozapine ​                    |
 |             ​| ​                            | Amisulpride ​                  | |             ​| ​                            | Amisulpride ​                  |
 +</​mobiletable>​
 </​panel>​ </​panel>​
 </​WRAP>​ </​WRAP>​
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 ===== Metabolism ===== ===== Metabolism =====
-<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​See also: **[[meds:​cytochrome-p450|]]**</​alert>​ +<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​ 
-Typical (first generation) ​antipsychotics are typically ​metabolized by CYP2D6. There is increased metabolism in Mediterranean populations. Clozapine and olanzapine (second generation antipsychotics) are metabolized by CYP1A2. +See also: **[[meds:​cytochrome-p450|]]** 
- +</​alert>​ 
-===== First (Typical) vs. Second (Atypical) Generation =====+  * Most antipsychotics are metabolized by CYP 2D6 and 3A4. 
 +    * Clozapine and olanzapine (second generation antipsychotics) are also metabolized by CYP1A2. 
 +  * There is increased metabolism in Mediterranean populations. 
 +===== Antipsychotic Classes ==== 
 +==== First (Typical) vs. Second (Atypical) Generation ==== 
 +<alert type="​info"​ icon="​fa fa-book fa-lg fa-fw">​See also Maudley'​s excellent discussion around this for more details ({{ :​meds:​antipsychotics:​fga_vs_sga_maudsley.pdf |PDF}})[(Taylor,​ David. Chapter 1, Schizophrenia. The Maudsley Prescribing Guidelines in Psychiatry, Twelfth Edition. pg. 16)] 
 +</​alert>​
  
 <WRAP group> <WRAP group>
 <WRAP half column> <WRAP half column>
-== What'​s ​the Difference? == +The first antipsychotics in the 1950s included chlorpromazine and haloperidol,​ and were called first-generation antipsychotics (FGAs), or typical antipsychotics. Starting in the 1990s, second-generation ​antipsychotics ​(SGAs) were released and marketedSGAs, also called ​atypical antipsychotics, ​were initially thought to be more effective ​and have a better safety profile. ​However, the [[teaching:​landmark-studies|landmark CATIE trial]] later showed that SGAs were no more effective than FGAs, and that the benefits ​were mainly [[teaching:​pharmaceutical-industry-influence|promoted by pharmaceutical companies]].[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​21813492|Lieberman,​ J. A., & Stroup, T. S. (2011). The NIMH-CATIE Schizophrenia Study: what did we learn?. American Journal of Psychiatry, 168(8), 770-775.]])] ​At the time of their releaseit was also thought that SGAs would cause less [[meds:antipsychotics:​eps|extrapyramidal symptoms]] (particularly tardive dyskinesia). This was also another initial reason behind categorizing antipsychotics as either typical (first generation) or atypical (second generation).
-In the 1990s, second-generation (i.e. - atypicalantipsychotics ​were introducedoffering the prospect of superior efficacy ​and a better safety profile. ​The landmark CATIE trial showed that atypical antipsychotics ​were no more effective than typicals, and that the benefits ​only promoted by pharmaceutical companies.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​21813492|Lieberman,​ J. A., & Stroup, T. S. (2011). The NIMH-CATIE Schizophrenia Study: what did we learn?. American Journal of Psychiatry, 168(8), 770-775.]])] ​ +
-Of note, the study showed that those receiving olanzapine experienced a longer ​time to discontinuationcompared with other antipsychotics, but they also had greater weight gain, hyperglycemia,​ and hyperlipidemia.+
  
-The propensity of an antipsychotic to cause [[meds:​antipsychotics:​eps|extrapyramidal symptoms]] (particularly tardive dyskinesia) was was also another reason behind categorizing antipsychotics as typical (first generation) or atypical (second generation). Generallyfirst generation (typical) antipsychotics ​have higher dopamine (D2) receptor occupancy and therefore have a higher risk of causing EPS. Second generation antipsychotics (atypical), more commonly ​have lower dopamine (D2) receptor occupancy, which results in lower incidence of EPS. These would include antipsychotics such as [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|clozapine]] and [[meds:​antipsychotics:​second-gen-atypical:​6-quetiapine|quetiapine]].+Thus//​generally//​ speaking: 
 +  * FGAs have higher dopamine (D2) receptor occupancy and therefore have a higher risk of causing EPS such as tardive dyskinesia 
 +  * SGAs usually ​have lower dopamine (D2) receptor occupancy, which results in lower incidence of EPS. These would include antipsychotics such as [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|clozapine]] and [[meds:​antipsychotics:​second-gen-atypical:​6-quetiapine|quetiapine]] 
 +    * However, distinction becomes blurred when considering higher potency SGAs which can also have moderate to high EPS effectsFor example, [[meds:​antipsychotics:​second-gen-atypical:​1-risperidone|risperidone]] at low doses (up to 3mg) does not cause EPS, and behaves like an SGA. But at higher doses (up to 16mg), it acts like an FGA, much like haloperidol,​ and the risk of EPS becomes equal 
 +  * SGAs also have greater antagonism for the serotonin receptor (5-HT2A) than the dopamine receptor (D2), and is why some SGAs, such as aripiprazole and quetiapine, are used in the treatment of mood disorders such as major depressive disorder and bipolar depression
  
-However, this distinction is blurred when factoring antipsychotics (both first and second generation) that have moderate EPS effects. One such example is [[meds:​antipsychotics:​second-gen-atypical:​1-risperidone|risperidone]],​ which at low doses (up to 3mg) does not cause EPS, and behaves like an atypical (second generation) antipsychotic. Beyond this, at higher doses (up to 16mg), it acts like a typical (first generation) antipsychotic,​ much like haloperidol,​ and the risk of EPS is the same. +At the present time, the difference ​between first and second generation ​antipsychotics is based more on historical ​and pharmaceutical influencerather than a black and white distinction. It is more important to look at an individual antipsychotic'​s ​potency, receptor profile, and pharmacokinetics,​ rather than if it is an FGA or SGA.
- +
-At the present time, the classification ​between first and second generation ​remains a product of historical ​traditionand the separation between the two classes is not black and white. It is more important to look at an individual antipsychotic'​s pharmacokinetics,​ rather than its classification. See Maudley'​s excellent discussion around this for more details ({{ :​meds:​antipsychotics:​fga_vs_sga_maudsley.pdf |PDF}})[(Taylor,​ David. Chapter 1, Schizophrenia. The Maudsley Prescribing Guidelines in Psychiatry, Twelfth Edition. pg16)]+
 </​WRAP>​ </​WRAP>​
 <WRAP half column> <WRAP half column>
- +<​catlist ​meds:​antipsychotics:​first-gen-typical ​-columns:1 -noAddPageButton -sortAscending>​ 
-~~DIR:::meds:​antipsychotics:​first-gen-typical?&​hdrs=First Generation~~ +<​catlist ​meds:​antipsychotics:​second-gen-atypical ​-columns:1 -noAddPageButton -sortAscending>
-~~DIR:::meds:​antipsychotics:​second-gen-atypical?&​hdrs=Second Generation~~ +
-<WRAP group> +
-<WRAP half column>​ +
- +
- +
-</​WRAP>​ +
-<WRAP half column>​ +
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-</​WRAP>​ +
-</​WRAP>​ +
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Line 99: Line 96:
  
 ===== Treatment ===== ===== Treatment =====
-== Efficacy == +==== Efficacy ​==== 
-Antipsychotics have a relatively quick onset of action and patients begin responding within 1 week.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​14662555|Agid,​ O., Kapur, S., Arenovich, T., & Zipursky, R. B. (2003). Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Archives of general psychiatry, 60(12), 1228-1235.]])] Patients first have experience better ​sleep due to the sedating effects of antipsychotics, ​then decreased anxiety occurs from resolution of the psychotic symptoms. ​Insight may take months ​to developif at all.+Antipsychotics have a relatively quick onset of action and patients begin responding within 1 week.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​14662555|Agid,​ O., Kapur, S., Arenovich, T., & Zipursky, R. B. (2003). Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Archives of general psychiatry, 60(12), 1228-1235.]])] Patients ​usually ​first have improved ​sleep due to the sedating effects of antipsychotics, ​followed by decreased anxiety occurs from resolution of the psychotic symptoms. ​Despite pharmaceutical company marketing, there is no evidence that first and second generation antipsychotics differ in efficacy. The only exception ​to this is clozapinewhich is the gold-standard medication for treatment-resistant schizophrenia,​ and has the lowest re-hospitalization rate compared to all other antipsychotics.
  
 +w
 ==== Length of Treatment ==== ==== Length of Treatment ====
-<alert icon="​fa fa-file-video-o ​fa-lg fa-fw" type="​success">​ +<​alert ​type="​info" ​icon="​fa fa-book fa-lg fa-fw">​ 
-See Video: **[[https://​www.youtube.com/​watch?​time_continue=1858&​v=VZrJftfZX3I|Reconsidering Medication Discontinuation After a First Episode of Psychosis]]**+See also: 
 +  * **[[https://​www.youtube.com/​watch?​v=VZrJftfZX3I|Reconsidering Medication Discontinuation After a First Episode of Psychosis]]** 
 +  * **[[https://​www.cambridge.org/​core/​journals/​psychological-medicine/​article/​antipsychotic-discontinuation-and-recovery-chicken-or-egg/​E23C9CD3987F7CA1374546CDD8020843|Pierre,​ J. M. et al. (2021). Antipsychotic discontinuation and recovery: chicken or egg?. Psychological Medicine, 1-2.]]**
 </​alert>​ </​alert>​
  
-How long should patients remain on antipsychotics for schizophrenia?​ The general consensus is that patients with chronic schizophrenia should remain on therapy long-term. However, there is some new evidence for //​first-episode//​ psychosis patients that "less is more."​[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​17502806|Harrow,​ M., & Jobe, T. H. (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications:​ a 15-year multifollow-up study. The Journal of nervous and mental disease, 195(5), 406-414.]])][([[http://​education.madinamerica.com/​p/​prescribing-antipsychotics-first-episode-psychosis|Wunderink,​ L. Prescribing Antipsychotics in First Episode Psychosis. Mad In America. (2013).]])][([[http://​jamanetwork.com/​journals/​jamapsychiatry/​fullarticle/​1707650|Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/​Discontinuation or Maintenance Treatment StrategyLong-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry. 2013;​70(9):​913–920.]])][([[https://​www.nimh.nih.gov/​about/​directors/​thomas-insel/​blog/​2013/​antipsychotics-taking-the-long-view.shtml|Insel,​ T. Post by Former NIMH Director Thomas Insel: Antipsychotics:​ Taking the Long View (2013).]])] ​This study observed that compared with a standard maintenance treatment regimen, dose reduction or supervised discontinuation of antipsychotic medication during the early phases of FEP led to a higher relapse rate initially, but improved long-term outcomes. This study has been criticized for its unequal distribution across diagnostic groups, high attrition rate, failure to separate the dose reduction and discontinuation groups, and the fact that most patients in each arm of the study did receive medication. ​These findings ​have not been replicatedMore importantly, clinicians and researchers are still unable to discern which populations will do well with an antipsychotic taper, and those who would worsen symptomatically. ​Studies ​are ongoing ​to investigate these questions.[([[https://​joannamoncrieff.com/​2016/​03/​02/​new-research-into-antipsychotic-discontinuation-and-reduction-the-radar-programme/​|Dr. Joanna Moncrieff - joannamoncrieff.com]])] Other more recent studies have shown that the risk of relapse after antipsychotic discontinuation does not decrease over time, and that antipsychotic use is associated with increased survival.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​29621900|Tiihonen,​ J., Tanskanen, A., & Taipale, H. (2018). 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. American Journal of Psychiatry, appi-ajp.]])] ​This indicates that long-term antipsychotic use for treating first-episode schizophrenia for the majority of patients remains ​the most evidence-based practice, as the relapse rates are greater than 80% with medication-discontinuation after several years. ​Relapse involves hospitalization,​ psychosis, and significant psychosocial impact, and this needs to be weighed carefully against discontinuation of medication. +  * How long should patients remain on antipsychotics for schizophrenia?​ The general consensus is that patients with chronic schizophrenia should remain on therapy long-term. However, there is some new evidence for //​first-episode//​ psychosis patients that "less is more."​[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​17502806|Harrow,​ M., & Jobe, T. H. (2007). Factors involved in outcome and recovery in schizophrenia patients not on antipsychotic medications:​ a 15-year multifollow-up study. The Journal of nervous and mental disease, 195(5), 406-414.]])][([[http://​jamanetwork.com/​journals/​jamapsychiatry/​fullarticle/​1707650|Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/​Discontinuation or Maintenance Treatment StrategyLong-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry. 2013;​70(9):​913–920.]])][([[https://​www.nimh.nih.gov/​about/​directors/​thomas-insel/​blog/​2013/​antipsychotics-taking-the-long-view.shtml|Insel,​ T. Post by Former NIMH Director Thomas Insel: Antipsychotics:​ Taking the Long View (2013).]])] 
- +  * A recent ​study observed that compared with a standard maintenance treatment regimen, dose reduction or supervised discontinuation of antipsychotic medication during the early phases of FEP led to a higher relapse rate initially, but improved long-term outcomes. This study has been criticized for its unequal distribution across diagnostic groups, high attrition rate, failure to separate the dose reduction and discontinuation groups, and the fact that most patients in each arm of the study still did receive medication.[([[http://​jamanetwork.com/​journals/​jamapsychiatry/​fullarticle/​1707650|Wunderink L, Nieboer RM, Wiersma D, Sytema S, Nienhuis FJ. Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/​Discontinuation or Maintenance Treatment StrategyLong-term Follow-up of a 2-Year Randomized Clinical Trial. JAMA Psychiatry. 2013;​70(9):​913–920.]])] 
-==== Monitoring ==== +    * Other studies ​have suggested that up to 40% of first episode psychosis patients are able to achieve good outcomes with either low or no doses of antipsychotics.[([[https://​pubmed.ncbi.nlm.nih.gov/​27802977/​|Murray,​ R. M., Quattrone, D., Natesan, S., van Os, J., Nordentoft, M., Howes, O., ... & Taylor, D. (2016). Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?​. The British Journal of Psychiatry, 209(5), 361-365.]])] 
-All patients who are on long-term antipsychotics must be medically monitored routinely. The following recommendations are from the {{ :​meds:​antipsychotics:​cpa_schizophrenia_guidelines_2005.pdf |2005 Canadian Psychiatric Association Clinical Practice Guidelines}}.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​16529334/​|Canadian Psychiatric Association. (2005). Clinical practice guidelines: treatment of schizophrenia. Canadian Journal of Psychiatry, 50(13), 7S.]])] +  * Yet other retrospective studies have shown that more breaks in antipsychotic treatments may result in greater risk of relapse and longer time to remission.[([[https://​pubmed.ncbi.nlm.nih.gov/​27745754/​|Winton-Brown,​ T. T., Elanjithara,​ T., Power, P., Coentre, R., Blanco-Polaina,​ P., & McGuire, P. (2017). Five-fold increased risk of relapse following breaks in antipsychotic treatment of first episode psychosis. Schizophrenia research, 179, 50-56.]])] 
- +  * Practically speaking, however, clinicians and researchers are still unable to discern which populations will do well with an antipsychotic taper, and those who would worsen symptomatically. 
-<panel type="​info"​ title="​Antipsychotic Monitoring"​ no-body="​true">​ +    * The 2023 RADAR Trial found that slow, supported dose reduction of antipsychotics was associated with a higher risk for relapse and did not result in improved social outcomes.[([[https://​www.thelancet.com/​journals/​lanpsy/​article/​PIIS2215-0366(23)00258-4/​fulltext|Moncrieff,​ J., Crellin, N., Stansfeld, J., Cooper, R., Marston, L., Freemantle, N., ... & Priebe, S. (2023). Antipsychotic dose reduction and discontinuation versus maintenance treatment in people with schizophrenia and other recurrent psychotic disorders in England (the RADAR trial): an open, parallel-group,​ randomised controlled trial. The Lancet Psychiatry.]])] 
-|                                                           ^ Initiation ​   ^ Acute phase                                                                                   ^ Maintenance phase                                               ^ +    * More studies ​are needed ​to investigate these very important clinical ​questions.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC5980442/​|Murray,​ R. M., & Di Forti, M. (2018). Increasing expectations and knowledge require a more subtle use of prophylactic antipsychotics. World Psychiatry, 17(2), 161.]])][([[https://​joannamoncrieff.com/​2016/​03/​02/​new-research-into-antipsychotic-discontinuation-and-reduction-the-radar-programme/​|Dr. Joanna Moncrieff - joannamoncrieff.com]])] Other more recent studies have shown that the risk of relapse after antipsychotic discontinuation does not decrease over time, and that antipsychotic use is associated with increased survival.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​29621900|Tiihonen,​ J., Tanskanen, A., & Taipale, H. (2018). 20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. American Journal of Psychiatry, appi-ajp.]])] 
-^ Electrolytes,​ Cr, LFTs, TSH                               | Always ​       | As clinically indicated ​                                                                      | As clinically indicated ​                                        | +  * Relapse involves hospitalization,​ recurrent psychosis, and significant psychosocial impact, and this needs to be weighed carefully against discontinuation of medication.  
-^ Fasting plasma glucose ​                                   | Always ​       | 4 months after initiating a new antipsychotic ​                                                | Every 1 year, or more often if symptomatic or increases in BMI  | +    * Thus, long-term antipsychotic use for treating first-episode schizophrenia for the majority of patients remains the most evidence-based practice, as the relapse rates are greater than 80% with medication-discontinuation after several years.
-^ HbA1c                                                     | Always ​       | Not required ​                                                                                 | Every 1 year                                                    | +
-^ Lipid panel (total cholesterol,​ LDL, HDL, triglycerides) ​ | Always ​       | Not required ​                                                                                 | Every 2 years, or every 6 months if the LDL is abnormal ​        | +
-^ Body mass (BMI)                                           | Always ​       | Before starting any new antipsychotic,​ then q6 months ​                                        | Every 3 months ​                                                 | +
-^ Extrapyramidal symptoms ​                                  | Always ​       | Before initiating a new antipsychotic,​ or when dosage is changed, then weekly for 2-4 weeks. ​ | Every 6 months, or more often for those at higher risk          | +
-^ Endocrine function (gynecomastia,​ galactorrhea,​ libido) ​  | Always ​       | Monthly for 3 months after starting an antipsychotic ​                                         | Every 1 year, order a prolactin level if clinically indicated ​  | +
-^ ECG                                                       | Not required ​ | If multiple QTc-affecting medications ​                                                        | As clinically indicated, or yearly ​                             | +
-</​panel>​ +
 ==== Long-Acting Injectables ==== ==== Long-Acting Injectables ====
 +<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​
 +See also: **[[meds:​antipsychotics:​0-long-acting-injectables|]]**
 +</​alert>​
 +
 The literature shows that clozapine and long-acting injectable antipsychotic medications have the highest rates of prevention of relapse in schizophrenia.[([[http://​psychiatrist.com/​JCP/​article/​Pages/​2013/​v74n10/​v74n1004.aspx|Kishimoto T, Nitta M, Borenstein M, Kane JM. The journal of clinical psychiatry: Long-acting injectable versus oral antipsychotics in schizophrenia:​ a systematic review and meta-analysis of mirror-image studies. Physicians Postgraduate Press Inc; 10/​01/​2013;​74:​957.]])] The risk of rehospitalization is about 20% to 30% for patients treated with long-acting injectable treatments compared with the oral equivalents.[([[http://​jamanetwork.com/​journals/​jamapsychiatry/​fullarticle/​2629295 The literature shows that clozapine and long-acting injectable antipsychotic medications have the highest rates of prevention of relapse in schizophrenia.[([[http://​psychiatrist.com/​JCP/​article/​Pages/​2013/​v74n10/​v74n1004.aspx|Kishimoto T, Nitta M, Borenstein M, Kane JM. The journal of clinical psychiatry: Long-acting injectable versus oral antipsychotics in schizophrenia:​ a systematic review and meta-analysis of mirror-image studies. Physicians Postgraduate Press Inc; 10/​01/​2013;​74:​957.]])] The risk of rehospitalization is about 20% to 30% for patients treated with long-acting injectable treatments compared with the oral equivalents.[([[http://​jamanetwork.com/​journals/​jamapsychiatry/​fullarticle/​2629295
 |Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtälä J, Hoti F, Jedenius E, Enkusson D, Leval A, Sermon J, Tanskanen A, Taipale H. Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia. JAMA Psychiatry. 2017;​74(7):​686–693.]])] If a patient is doing well on an existing first-generation long-acting injectable, switching them to a second-generation LAI puts them at a higher risk of treatment discontinuation and weight gain.[([[http://​www.psychiatrist.com/​JCP/​article/​Pages/​2012/​v73n05/​v73n0515.aspx|| |Tiihonen J, Mittendorfer-Rutz E, Majak M, Mehtälä J, Hoti F, Jedenius E, Enkusson D, Leval A, Sermon J, Tanskanen A, Taipale H. Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia. JAMA Psychiatry. 2017;​74(7):​686–693.]])] If a patient is doing well on an existing first-generation long-acting injectable, switching them to a second-generation LAI puts them at a higher risk of treatment discontinuation and weight gain.[([[http://​www.psychiatrist.com/​JCP/​article/​Pages/​2012/​v73n05/​v73n0515.aspx||
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 ==== Polypharmacy ==== ==== Polypharmacy ====
-Antipsychotic polypharmacy (i.e. - taking more than 1 antipsychotic) is commonly seen, but should not occur! ​Patients ​with antipsychotic polypharmacy should be transitioned to monotherapy treatment. Furthermore,​ changing to monotherapy does not compromise the clinical response.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​26845273| Borlido, C., Remington, G. et al. (2016). Switching from 2 antipsychotics to 1 antipsychotic in schizophrenia:​ a randomized, double-blind,​ placebo-controlled study. The Journal of clinical psychiatry, 77(1), e14-20]])] ​Some patients may be on multiple antipsychotics due to treatment resistancehoweverthis should be a treatment of last resort.+Antipsychotic polypharmacy (i.e. - taking more than 1 antipsychotic) is commonly seen, but really ​should not occur! ​Generally speaking, patients ​with antipsychotic polypharmacy should be transitioned to monotherapy treatment. Furthermore,​ changing to monotherapy does not compromise the clinical response.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​26845273| Borlido, C., Remington, G. et al. (2016). Switching from 2 antipsychotics to 1 antipsychotic in schizophrenia:​ a randomized, double-blind,​ placebo-controlled study. The Journal of clinical psychiatry, 77(1), e14-20]])] ​One recent cohort studies did show superiority of clozapine plus aripiprazole over clozapine alone.[([[https://​pubmed.ncbi.nlm.nih.gov/​30785608/​|TiihonenJ.Taipale, H., Mehtälä, J., Vattulainen,​ P., Correll, C. U., & Tanskanen, A. (2019). Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA psychiatry, 76(5), 499-507.]])] However, antipsychotic polypharmacy ​should ​always ​be a treatment of last resort.
  
 ==== Switching/​Tapering ==== ==== Switching/​Tapering ====
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 ==== Discontinuation ==== ==== Discontinuation ====
-<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​See also: **[[meds:​antipsychotics:​neuroleptic-induced-dopamine-supersensitivity-psychosis-dsp]]**</​alert>​+<alert icon="​fa fa-arrow-circle-right fa-lg fa-fw" type="​success">​See also: **[[meds:​antipsychotics:​dopamine-supersensitivity-psychosis-dsp]]**</​alert>​
 Discontinuation of antipsychotics is often a patient request due to intolerable side effects from the medication. This can present as a challenging clinical decision.[([[https://​www.nature.com/​articles/​s41537-016-0004-2|Emsley,​ R. (2017). On discontinuing treatment in schizophrenia:​ a clinical conundrum.]])] Rapid or abrupt antipsychotic discontinuation is one of the major reasons for symptom recurrence and readmission to hospital. Therefore, any discontinuation should be carefully monitored and tapered slowly. The abrupt withdrawal of clozapine has been associated with cholinergic rebound and rapid onset of psychosis. Discontinuation-induced supersensitivity of dopamine receptors can lead to worsening and the appearance of new and more complex symptoms.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​8938913|Shiovitz,​ T. M., Welke, T. L., Tigel, P. D., Anand, R., Hartman, R. D., Sramek, J. J., ... & Cutler, N. R. (1996). Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophrenia bulletin, 22(4), 591.]])] Therefore, clozapine should always be gradually and slowly tapered over time. Discontinuation of antipsychotics is often a patient request due to intolerable side effects from the medication. This can present as a challenging clinical decision.[([[https://​www.nature.com/​articles/​s41537-016-0004-2|Emsley,​ R. (2017). On discontinuing treatment in schizophrenia:​ a clinical conundrum.]])] Rapid or abrupt antipsychotic discontinuation is one of the major reasons for symptom recurrence and readmission to hospital. Therefore, any discontinuation should be carefully monitored and tapered slowly. The abrupt withdrawal of clozapine has been associated with cholinergic rebound and rapid onset of psychosis. Discontinuation-induced supersensitivity of dopamine receptors can lead to worsening and the appearance of new and more complex symptoms.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​8938913|Shiovitz,​ T. M., Welke, T. L., Tigel, P. D., Anand, R., Hartman, R. D., Sramek, J. J., ... & Cutler, N. R. (1996). Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Schizophrenia bulletin, 22(4), 591.]])] Therefore, clozapine should always be gradually and slowly tapered over time.
 +
 +===== Monitoring =====
 +<alert type="​info"​ icon="​fa fa-book fa-lg fa-fw">​
 +See also: **[[meds:​antipsychotics:​metabolic-syndrome|]]**
 +</​alert>​
 +
 +All patients who are on long-term antipsychotics must be medically monitored routinely.
 +
 +<panel type="​info"​ title="​Antipsychotic Monitoring"​ no-body="​true"​ subtitle="​Adapted from: Pringsheim, T. et al. (2017) Physical health and drug safety in individuals with schizophrenia. The Canadian Journal of Psychiatry, 62(9), 673-683.">​
 +<​mobiletable 1>
 +^                                                                  ^ Initiation ​                                                                        ^ 1 month after initiation ​ ^ 3 months after initiation ​                                                ^ Then annually ​                      ^
 +^ Electrolytes,​ Cr, LFTs, TSH                                      | ✓                                                                                  | As clinically indicated ​  | As clinically indicated ​                                                  | As clinically indicated ​            |
 +^ Fasting plasma glucose ​                                          | ✓                                                                                  | As clinically indicated ​  | ✓                                                                         | ✓                                   |
 +^ HbA1c                                                            | ✓                                                                                  | -                         | ✓                                                                         | ✓                                   |
 +^ Lipid panel (total cholesterol,​ LDL, HDL, triglycerides) ​        | ✓                                                                                  | As clinically indicated ​  | ✓                                                                         | ✓                                   |
 +^ Body mass (BMI)                                                  | ✓                                                                                  | ✓                         | ✓                                                                         | ✓                                   |
 +^ Blood pressure (BP)                                              | ✓                                                                                  | As clinically indicated ​  | ✓                                                                         | ✓                                   |
 +^ [[meds:​antipsychotics:​eps|Extrapyramidal symptom (EPS) exam]] ​   | ✓                                                                                  | ✓                         | ✓                                                                         | ✓                                   |
 +^ Endocrine function history (gynecomastia,​ galactorrhea,​ libido) ​ | ✓                                                                                  | -                         | ✓                                                                         | ✓                                   |
 +^ [[meds:​antipsychotics:​hyperprolactinemia|Prolactin]] ​            | If clinically indicated ​                                                           | If clinically indicated ​  | If clinically indicated ​                                                  | If clinically indicated ​            |
 +^ [[meds:​qtc|ECG (QT monitoring)]] ​                                | If clinically indicated (some clinicians will order this routinely as a baseline) ​ | -                         | If on multiple QTc-prolonging medications\\ (or if clinically indicated) ​ | As clinically indicated, or yearly ​ |
 +^ [[addictions:​nicotine-tobacco:​1-use-disorder|Smoking history]] ​  | ✓                                                                                  | -                         | ✓                                                                         | ✓                                   |
 +</​mobiletable>​
 +</​panel>​
 +
  
 ===== Side Effects and Adverse Events ===== ===== Side Effects and Adverse Events =====
-**Antipsychotics are not benign, and must be used judiciously.** The main side effects include extrapyramidal symptoms and sexual side effects,​[([[https://​www.ncbi.nlm.nih.gov/​books/​NBK448156/​|Vasan,​ S., & Abdijadid, S. (2017). Atypical antipsychotic agents. In StatPearls [Internet]. StatPearls Publishing.]])] (due to potent dopamine receptor blockade), anticholingeric side effects like sedation (from blockade of histaminergic and muscarinic receptors), and cardiovascular (from adrenergic blockade).[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3657088/​|Scigliano,​ G., & Ronchetti, G. (2013). Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia:​ a novel mechanistic hypothesis. CNS drugs, 27(4), 249-257.]])] Adverse reactions include [[meds:​antipsychotics:​nms-neuroleptic-malignant-syndrome|neuroleptic malignant syndrome]], seizures, and cardiovascular problems.+**Antipsychotics are not benign, and must be used judiciously.** The main side effects include extrapyramidal symptoms and sexual side effects,​[([[https://​www.ncbi.nlm.nih.gov/​books/​NBK448156/​|Vasan,​ S., & Abdijadid, S. (2017). Atypical antipsychotic agents. In StatPearls [Internet]. StatPearls Publishing.]])] (due to potent dopamine receptor blockade), anticholingeric side effects like sedation (from blockade of histaminergic and muscarinic receptors), and cardiovascular (from anticholinergic effects and adrenergic blockade).[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3657088/​|Scigliano,​ G., & Ronchetti, G. (2013). Antipsychotic-induced metabolic and cardiovascular side effects in schizophrenia:​ a novel mechanistic hypothesis. CNS drugs, 27(4), 249-257.]])] Adverse reactions include [[meds:​antipsychotics:​nms-neuroleptic-malignant-syndrome|neuroleptic malignant syndrome]], seizures, and cardiovascular problems. The reason for many of the side effects associated with antipsychotics is because antipsychotics do not exclusively target the dopamine receptors, and other receptors are also targeted.
  
-<panel type="​info"​ title="​Side Effects ​and Adverse Events ​Associated with Antipsychotics"​ subtitle=""​ no-body="​true"​ footer="">​+==== Side Effects ==== 
 +<alert type="​info"​ icon="​fa fa-book fa-lg fa-fw">​ 
 +See also article: **[[https://​pubmed.ncbi.nlm.nih.gov/​30192094/​|Stroup,​ T. S., & Gray, N. (2018). Management of common adverse effects of antipsychotic medications. World Psychiatry, 17(3), 341-356.]]** 
 +</​alert>​ 
 + 
 +<panel type="​info"​ title="​Side Effects Associated with Antipsychotics"​ subtitle=""​ no-body="​true"​ footer=""​
 +<​mobiletable 1>
 ^ Side Effects ​                                                   ^ Description ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      ^ Management ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               ^ ^ Side Effects ​                                                   ^ Description ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      ^ Management ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               ^
-^ [[meds:​antipsychotics:​eps]] ​                                    | Extrapyramidal side effects include acute dystonia, akathisia, neuroleptic-induced parkinsonism,​ tardive dyskinesia, and tardive dystonia. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | See [[meds:​antipsychotics:​eps|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | +^ [[meds:​antipsychotics:​metabolic-syndrome]] ​                     | Atypical antipsychotics can cause hypertension,​ high blood sugar, obesity, and abnormal cholesterol or triglyceride levelsresulting in metabolic syndrome. Patients on atypical antipsychotics should be routinely monitored with metabolic blood work.                                                                                                                                                                                                                                                                                                                                                                                         | See [[meds:​antipsychotics:​metabolic-syndrome|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 
-^ [[meds:​antipsychotics:​metabolic-syndrome]] ​                     | Atypical antipsychotics can cause hypertension,​ high blood sugar, obesity, and abnormal cholesterol or triglyceride levelsresulting in metabolic syndrome. Patients on atypical antipsychotics should be routinely monitored with metabolic blood work.                                                                                                                                                                                                                                                                                                                                                                                         | See [[meds:​antipsychotics:​metabolic-syndrome|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | +[[meds:​antipsychotics:​constipation|Constipation]]               | Chronic antipsychotic use can lead to constipation,​ which can be severe. Constipation can be a serious and life-threatening issue for patients on [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine#​constipation|clozapine]]. ​                                                                                                                                                                                                                                                                                                                                                                                                                | First-line management and treatment includes the use of an osmotic agent, such as polyethylene glycol (PEG), and/or a stimulant laxative such as senna. There is limited evidence for the use of surfactant agents (“stool softeners”) like docusate sodium for chronic constipation. These agents only lower the surface tension of stool, but are not effective at preventing and treating medication-induced constipation. Patients on [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine#​constipation|clozapine]] need to have regular bowel monitoring as the risks of complications are higher! ​ |
-^ Constipation ​                                                   | Chronic antipsychotic use can lead to constipation,​ which can be severe. Constipation can be a serious and life-threatening issue for patients on [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine#​constipation|clozapine]]. ​                                                                                                                                                                                                                                                                                                                                                                                                                | First-line management and treatment includes the use of an osmotic agent, such as polyethylene glycol (PEG), and/or a stimulant laxative such as senna. There is limited evidence for the use of surfactant agents (“stool softeners”) like docusate sodium for chronic constipation. These agents only lower the surface tension of stool, but are not effective at preventing and treating medication-induced constipation. Patients on [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine#​constipation|clozapine]] need to have regular bowel monitoring as the risks of complications are higher! ​ |+
 ^ Sedation ​                                                       | Certain antipsychotics are more sedating than others. The degree of sedation depends on the affinity to the histamine (H1) receptor. Generally, low potency antipsychotics are more sedating than high potency ones, and atypicals are more sedating than typicals. The most -> least sedating antipsychotics (by H1 receptor affinity) are: clozapine > olanzapine > quetiapine > risperidone.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC487011/​|Miller,​ D. D. (2004). Atypical antipsychotics:​ sleep, sedation, and efficacy. Primary care companion to the Journal of clinical psychiatry, 6(suppl 2), 3.]])] ​                           | Reduce dose or consider antipsychotic switch to a higher potency antipsychotic. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | ^ Sedation ​                                                       | Certain antipsychotics are more sedating than others. The degree of sedation depends on the affinity to the histamine (H1) receptor. Generally, low potency antipsychotics are more sedating than high potency ones, and atypicals are more sedating than typicals. The most -> least sedating antipsychotics (by H1 receptor affinity) are: clozapine > olanzapine > quetiapine > risperidone.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC487011/​|Miller,​ D. D. (2004). Atypical antipsychotics:​ sleep, sedation, and efficacy. Primary care companion to the Journal of clinical psychiatry, 6(suppl 2), 3.]])] ​                           | Reduce dose or consider antipsychotic switch to a higher potency antipsychotic. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
-^ [[meds:​antipsychotics:​nms-neuroleptic-malignant-syndrome]] ​     | NMS is a life-threatening idiosyncratic reaction to antipsychotics characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. It is hypothesized to be due to excessive dopamine receptor blockade. Certain individuals may be at a higher risk for NMS.                                                                                                                                                                                                                                                                                                                                                          | See [[meds:​antipsychotics:​nms-neuroleptic-malignant-syndrome|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | 
 ^ [[meds:​antipsychotics:​hyperprolactinemia]] ​                     | Hyperprolactinemia can be completely asymptomatic or be very distressing to patients when they experience associated symptoms including: menstrual disturbances,​ anovulatory cycles, galactorrhea,​ impaired fertility, or sexual dysfunction. It is due to the blockade of the tuberoinfundibular pathway. ​                                                                                                                                                                                                                                                                                                                                       | See [[meds:​antipsychotics:​hyperprolactinemia|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | ^ [[meds:​antipsychotics:​hyperprolactinemia]] ​                     | Hyperprolactinemia can be completely asymptomatic or be very distressing to patients when they experience associated symptoms including: menstrual disturbances,​ anovulatory cycles, galactorrhea,​ impaired fertility, or sexual dysfunction. It is due to the blockade of the tuberoinfundibular pathway. ​                                                                                                                                                                                                                                                                                                                                       | See [[meds:​antipsychotics:​hyperprolactinemia|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
-^ Amenorrhea ​                                                     | In females, hyperprolactinemia can result in amenorrhea, potentially causing ovarian dysfunction or infertility. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Metformin can restore menstruation in obese women with amenorrhea by restoring sex hormone levels and decreasing insulin resistance.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​22711171|Wu,​ R. R., Jin, H., Gao, K., Twamley, E. W., Ou, J. J., Shao, P., ... & Zhao, J. P. (2012). Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia:​ a double-blind,​ randomized, placebo-controlled study. American Journal of Psychiatry, 169(8), 813-821.]])] Asking for a menstrual history is thus important for females on antipsychotics. ​       |+[[meds:​antipsychotics:​hyperprolactinemia|Amenorrhea]]           | In females, hyperprolactinemia can result in amenorrhea, potentially causing ovarian dysfunction or infertility. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Metformin can restore menstruation in obese women with amenorrhea by restoring sex hormone levels and decreasing insulin resistance.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​22711171|Wu,​ R. R., Jin, H., Gao, K., Twamley, E. W., Ou, J. J., Shao, P., ... & Zhao, J. P. (2012). Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia:​ a double-blind,​ randomized, placebo-controlled study. American Journal of Psychiatry, 169(8), 813-821.]])] Asking for a menstrual history is thus important for females on antipsychotics. ​       |
 ^ [[meds:​antidepressants:​sexual-dysfunction|Sexual Dysfunction]] ​ | Sexual dysfunction is common condition in patients taking antipsychotics,​ and caused by hyperprolactinemia and dopamine blockade.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​23596605|Park,​ Y. W., Kim, Y., & Lee, J. H. (2012). Antipsychotic-induced sexual dysfunction and its management. The world journal of men's health, 30(3), 153-159.]])] It is also the most bothersome symptom for patients. Sildenafil can be prescribed as a treatment for sexual dysfunction. ​                                                                                                                                                                        | See [[meds:​antidepressants:​sexual-dysfunction|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | ^ [[meds:​antidepressants:​sexual-dysfunction|Sexual Dysfunction]] ​ | Sexual dysfunction is common condition in patients taking antipsychotics,​ and caused by hyperprolactinemia and dopamine blockade.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​23596605|Park,​ Y. W., Kim, Y., & Lee, J. H. (2012). Antipsychotic-induced sexual dysfunction and its management. The world journal of men's health, 30(3), 153-159.]])] It is also the most bothersome symptom for patients. Sildenafil can be prescribed as a treatment for sexual dysfunction. ​                                                                                                                                                                        | See [[meds:​antidepressants:​sexual-dysfunction|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
-Cardiac Risks and [[meds:​qtc|QTc Prolongation]] ​                ​| Antipsychotic increase the risk of ventricular arrhythmias,​ through the blockade of potassium channels and prolongation of the QT interval (i.e. - cardiac re-polarization). Other mechanisms may be involved, including autonomic effects and inhibition of other ion channels. [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|Clozapine]] is also associated with myocarditis,​ which is not seen with other antipsychotics.[([[http://​www.nejm.org/​doi/​full/​10.1056/​NEJMoa0806994|Ray,​ Wayne A., et al. "​Atypical antipsychotic drugs and the risk of sudden cardiac death."​ New England Journal of Medicine 360.3 (2009): 225-235.]])] ​ | See [[meds:​qtc|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            +Hypotension ​                                                    | Orthostatic hypotension can be common in atypical antipsychotics (ranging from paliperidone to clozapine). It is thought to be caused by anticholinergic effects ​and/or alpha-1 adrenoceptor blockade.[([[https://​pubmed.ncbi.nlm.nih.gov/​21790209/​|Gugger,​ J. J. (2011). Antipsychotic pharmacotherapy and orthostatic hypotension. CNS drugs, 25(8), 659-671.]])] ​                                                                                                                                                                                                                                                                              | Consider adjusting the dose, increasing hydration, or change to a less anticholinergic antipsychotic (i.e. switching from low potency to high potency) ​                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 
-^ Seizures ​                                                       | Both typicals and atypicals can lower the seizure threshold. With typicals, chlorpromazine has the highest risk of inducing seizures, while haloperidol,​ fluphenazine,​ pimozide and trifluoperazine are associated with a lower risk of seizure. With atypicals, clozapine is commonly associated with seizures, while risperidone has the lowest risk.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​12973403|Hedges,​ D., Jeppson, K., & Whitehead, P. (2003). Antipsychotic medication and seizures: a review. Drugs Today (Barc), 39(7), 551-557.]])] ​                                                                                                | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |+^ Tachycardia ​                                                    | Tachycardia can result from low potency antipsychotics that have a higher anticholinergic burden. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Consider adjusting the dose, or changing to a less anticholinergic antipsychotic. In severe cases, tachycardia can be treated with beta‐blocker ​                                                                                                                                                                                                                                                                                                                                                                                                                                                          | 
 +[[meds:​qtc|QTc Prolongation]] ​                                  ​| Antipsychotic increase the risk of ventricular arrhythmias,​ through the blockade of potassium channels and prolongation of the QT interval (i.e. - cardiac re-polarization). Other mechanisms may be involved, including autonomic effects and inhibition of other ion channels. [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|Clozapine]] is also associated with myocarditis,​ which is not seen with other antipsychotics.[([[http://​www.nejm.org/​doi/​full/​10.1056/​NEJMoa0806994|Ray,​ Wayne A., et al. "​Atypical antipsychotic drugs and the risk of sudden cardiac death."​ New England Journal of Medicine 360.3 (2009): 225-235.]])] ​ | See [[meds:​qtc|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
 ^ SIADH and [[cl:​hyponatremia|]] ​                                 | In rare cases, antipsychotics can cause hyponatremia.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​16999280|Kenes,​ M. T., Hamblin, S. E., Tumuluri, S. S., & Guillamondegui,​ O. D. (2016). Syndrome of Inappropriate Antidiuretic Hormone in a Patient Receiving High-Dose Haloperidol and Quetiapine Therapy. The Journal of neuropsychiatry and clinical neurosciences,​ 28(2), e29-e30.]])] Antipsychotics are thought to increase AVP release is increased despite normal plasma osmolality, resulting in syndrome of inappropriate antidiuretic hormone secretion (SIADH), which can result in hyponatremia. ​                                       | See [[cl:​hyponatremia|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | ^ SIADH and [[cl:​hyponatremia|]] ​                                 | In rare cases, antipsychotics can cause hyponatremia.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​16999280|Kenes,​ M. T., Hamblin, S. E., Tumuluri, S. S., & Guillamondegui,​ O. D. (2016). Syndrome of Inappropriate Antidiuretic Hormone in a Patient Receiving High-Dose Haloperidol and Quetiapine Therapy. The Journal of neuropsychiatry and clinical neurosciences,​ 28(2), e29-e30.]])] Antipsychotics are thought to increase AVP release is increased despite normal plasma osmolality, resulting in syndrome of inappropriate antidiuretic hormone secretion (SIADH), which can result in hyponatremia. ​                                       | See [[cl:​hyponatremia|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
 +^ Sialorrhea (Hypersalivation) ​                                   | Hypersalivation/​sialorrhea is a common side effect related to clozapine use (but can also occur in other antipsychotics). Sialorrhea can range from being mildly uncomfortable drooling to potentially life-threatening conditions, such as parotitis, choking, and aspiration. ​                                                                                                                                                                                                                                                                                                                                                                  | See [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine#​salivation-hypersialorrhea|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
 +</​mobiletable>​
 </​panel>​ </​panel>​
  
 +==== Adverse Events ====
 +<panel type="​info"​ title="​Adverse Events Associated with Antipsychotics"​ subtitle=""​ no-body="​true"​ footer="">​
 +<​mobiletable 1>
 +^ Side Effects ​                                                   ^ Description ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      ^ Management ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               ^
 +^ [[meds:​antipsychotics:​eps]] ​                                    | Extrapyramidal side effects include acute dystonia, akathisia, neuroleptic-induced parkinsonism,​ tardive dyskinesia, and tardive dystonia. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | See [[meds:​antipsychotics:​eps|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
 +^ [[meds:​antipsychotics:​nms-neuroleptic-malignant-syndrome]] ​     | NMS is a life-threatening idiosyncratic reaction to antipsychotics characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. It is hypothesized to be due to excessive dopamine receptor blockade. Certain individuals may be at a higher risk for NMS.                                                                                                                                                                                                                                                                                                                                                          | See [[meds:​antipsychotics:​nms-neuroleptic-malignant-syndrome|main article]] ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
 +^ Seizures ​                                                       | Both typicals and atypicals can lower the seizure threshold. With typicals, chlorpromazine has the highest risk of inducing seizures, while haloperidol,​ fluphenazine,​ pimozide and trifluoperazine are associated with a lower risk of seizure. With atypicals, clozapine is commonly associated with seizures, while risperidone has the lowest risk.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​12973403|Hedges,​ D., Jeppson, K., & Whitehead, P. (2003). Antipsychotic medication and seizures: a review. Drugs Today (Barc), 39(7), 551-557.]])] ​                                                                                                | -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
 +</​mobiletable>​
 +</​panel>​
 ===== Special Populations ===== ===== Special Populations =====
-<callout ​type="success">{{fa>​arrow-circle-right?color=green}} ​See also articles: **[[meds:​pharmacology:​geri]] and [[meds:​pharmacology:​obstetric-and-fetal]] **</callout>+<alert type="info" icon="​fa ​fa-book fa-lg fa-fw"> 
 +See also: **[[http://​www.bcchildrens.ca/​mental-health-services-site/​Documents/​physicianhandbookformetabolicmonitoring.pdf|BC Children'​s Hospital A Physician Handbook for Metabolic Monitoring for Youth with Mental Illness treated with Second-Generation Antipsychotics]]** 
 +</​alert>​ 
 + 
 +<alert icon="​fa fa-arrow-circle-right ​fa-lg fa-fw" type="​success">​ 
 +See main articles: **[[meds:​pharmacology:​geri]] and [[meds:​pharmacology:​obstetric-and-fetal]]** 
 +</alert> 
 <panel title="​Special Populations"​ type="​info"​ no-body="​true">​ <panel title="​Special Populations"​ type="​info"​ no-body="​true">​
-^ Population ​         ^ Considerations ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           +^ Population ​                                                             ^ Considerations ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
-^ Elderly ​            ​| **All** antipsychotic agents are associated with increased risk of mortality in elderly patients with dementia.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​16319382|Wang,​ P. S., Schneeweiss,​ S., Avorn, J., Fischer, M. A., Mogun, H., Solomon, D. H., & Brookhart, M. A. (2005). Risk of death in elderly users of conventional vs. atypical antipsychotic medications. New England Journal of Medicine, 353(22), 2335-2341.]])] There is also an increased incidence of cerebrovascular events (e.g. TIAs, stroke) has been seen among elderly patients on antipsychotics. When benefits outweigh risks, use lower doses, slower titration schedules, and periodic reassessment for the necessity of the medication ​  ​+[[meds:​pharmacology:​geri|Elderly]]                                      ​| **All** antipsychotic agents are associated with increased risk of mortality in elderly patients with dementia.[([[https://​www.ncbi.nlm.nih.gov/​pubmed/​16319382|Wang,​ P. S., Schneeweiss,​ S., Avorn, J., Fischer, M. A., Mogun, H., Solomon, D. H., & Brookhart, M. A. (2005). Risk of death in elderly users of conventional vs. atypical antipsychotic medications. New England Journal of Medicine, 353(22), 2335-2341.]])] There is also an increased incidence of cerebrovascular events (e.g. TIAs, stroke) has been seen among elderly patients on antipsychotics. When benefits outweigh risks, use lower doses, slower titration schedules, and periodic reassessment for the necessity of the medication ​ 
-^ Pediatric and Youth    | Children and youth who are on second generation antipsychotics must have close metabolic monitoring. ​See [[http://​www.bcchildrens.ca/​mental-health-services-site/​Documents/​physicianhandbookformetabolicmonitoring.pdf|BC Children'​s Hospital A Physician Handbook for Metabolic Monitoring for Youth with Mental Illness treated with Second-Generation Antipsychotics]]                                                                                                      | +[[meds:​pharmacology:​pediatric|Pediatric and Youth]]                     | Children and youth who are on second generation antipsychotics must have close metabolic monitoring. ​                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | 
-^ Renal Impairment ​   | All first generation antipsychotics can be used with caution in those with renal impairment without dosage adjustment. However, recommend initiation at lowest dose (especially in patients with concurrent hepatic impairment). Second generation antipsychotics must be carefully titrated.[([[https://​www.hopkinsguides.com/​hopkins/​view/​Johns_Hopkins_Diabetes_Guide/​547011/​all/​Antipsychotics|Johns Hopkins Diabetes Guide - Antipsychotics]])] ​                                                                                                     +[[meds:pharmacology:​psychotropic-rx-medically-ill|Renal Impairment]]    | All first generation antipsychotics can be used with caution in those with renal impairment without dosage adjustment. However, recommend initiation at lowest dose (especially in patients with concurrent hepatic impairment). Second generation antipsychotics must be carefully titrated.[([[https://​www.hopkinsguides.com/​hopkins/​view/​Johns_Hopkins_Diabetes_Guide/​547011/​all/​Antipsychotics|Johns Hopkins Diabetes Guide - Antipsychotics]])] ​                                                                                                                                                                                                                                                               
-^ Hepatic Impairment ​ | No dosage adjustment necessary for use of the first generation antipsychotics. However, recommend initiation at lowest dose (especially in patients with concurrent renal impairment). Asenapine, lurasidone, paliperidone,​ and risperidone should be avoided in those with severe hepatic impairment.[([[https://​www.hopkinsguides.com/​hopkins/​view/​Johns_Hopkins_Diabetes_Guide/​547011/​all/​Antipsychotics|Johns Hopkins Diabetes Guide - Antipsychotics]])] ​                                                                                            ​+[[meds:​pharmacology:​psychotropic-rx-medically-ill|Hepatic Impairment]]  | No dosage adjustment necessary for use of the first generation antipsychotics. However, recommend initiation at lowest dose (especially in patients with concurrent renal impairment). Asenapine, lurasidone, paliperidone,​ and risperidone should be avoided in those with severe hepatic impairment.[([[https://​www.hopkinsguides.com/​hopkins/​view/​Johns_Hopkins_Diabetes_Guide/​547011/​all/​Antipsychotics|Johns Hopkins Diabetes Guide - Antipsychotics]])] ​                                                                                                                                                                                                                                                      ​
-^ Pregnancy ​          ​| Only clozapine and lurasidone are FDA Risk Category B (safe for use in pregnancy, but limited human data available; use with caution). All other antipsychotics are FDA Risk Category C (not safe in pregnancy, use only if benefit outweighs risk). All antipsychotics are also proven, or presumed, to be excreted into breast milk. Breastfeeding while on antipsychotics is not recommended.[([[https://​www.hopkinsguides.com/​hopkins/​view/​Johns_Hopkins_Diabetes_Guide/​547011/​all/​Antipsychotics|Johns Hopkins Diabetes Guide - Antipsychotics]])] ​ |+[[meds:​pharmacology:​obstetric-and-fetal|Pregnancy]]                     | Only clozapine and lurasidone are FDA Risk Category B (safe for use in pregnancy, but limited human data available; use with caution). All other antipsychotics are FDA Risk Category C (not safe in pregnancy, use only if benefit outweighs risk). All antipsychotics are also proven, or presumed, to be excreted into breast milk. Breastfeeding while on antipsychotics is not recommended.[([[https://​www.hopkinsguides.com/​hopkins/​view/​Johns_Hopkins_Diabetes_Guide/​547011/​all/​Antipsychotics|Johns Hopkins Diabetes Guide - Antipsychotics]])] ​                                                                                                                                                            ​|
 </​panel>​ </​panel>​
 +
 ===== Controversy ===== ===== Controversy =====
-== Brain Volume == +<alert type="​info"​ icon="fa fa-book fa-lg fa-fw">​ 
-What is the effect of antipsychotics on brain volume? A controversial paper came out in 2011[([[https://www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3476840/|Ho B-CAndreasen NC, Ziebell S, Pierson ​R, Magnotta V. Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia. Archives of general psychiatry2011;68(2):128-137doi:​10.1001/​archgenpsychiatry.2010.199.]])] that suggested ​antipsychotics ​were linked to smaller gray matter volumesWhat the paper did not address is what the actual clinical significance of this means for patients ​(i.e. - is this a good thing or a bad thing?). Since that papermultiple recent studies have shown the opposite findings: that brain volume and cortical changes are //not// explained by exposure to antipsychotic drugs, but likely due to the pathophysiology behind psychosis.[([[https://www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC4264996/|CannonTyrone D. +See also:  
- et al. “Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk.” Biological psychiatry 77.2 (2015): 147–157. PMC. Web. 13 Sept. 2017.]])][([[http://​journals.plos.org/​plosone/​article?​id=10.1371/​journal.pone.0101689|VeijolaJuhaet al"​Longitudinal changes in total brain volume in schizophrenia:​ relation to symptom severitycognition and antipsychotic medication."​ PLoS One 9.(2014): e101689.]])] Other brain research studies have shown that unaffected first-degree relatives of schizophrenics also have thinner cortical volume.[([[http://​www.pnas.org/​content/​99/​5/​3228.short|CannonTyrone D., et al. "​Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia."​ Proceedings of the National Academy of Sciences 99.5 (2002): 3228-3233.]])] Clearly, there are implications from this research, and there should continue to be more research on the effects of antipsychotics on the brain. What is clear is that at this time, there are no clear indications what brain volume changes clinically means for patients. The current and overall research evidence suggests that global neuronal dysfunction from psychosis and schizophrenia better explains cortical thinning and brain volume loss, rather than from antipsychotic use.+  * **[[https://pubmed.ncbi.nlm.nih.gov/​33050955/|Whitaker, R. (2020). do antipsychotics ​protect against early death? A critical viewPsychological Medicine, 50(16), 2643-2652.]]** 
 +  * **[[https://pubmed.ncbi.nlm.nih.gov/​33100236/|TiihonenJ., TaipaleH., & Correll, CU. (2020). Commentary on Robert Whitaker'​s viewpointPsychological Medicine1-2.]]**
  
-== Mortality == +</​alert>​ 
-There is no significant difference in the incidence of all-cause death and death due to suicide between oral psychotics, injection antipsychotics,​ and placebo.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC5049525/​|Kishi,​ T., Matsunaga, S., & Iwata, N. (2016). Mortality risk associated with long-acting injectable antipsychotics:​ a systematic review and meta-analyses of randomized controlled trials. Schizophrenia bulletin, 42(6), 1438-1445.]])]+ 
 +==== Brain Volume ==== 
 +An initially controversial paper came out in 2011 that suggested antipsychotics were linked to smaller gray matter volumes.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC3476840/​|Ho B-C, Andreasen NC, Ziebell S, Pierson R, Magnotta V. Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia. Archives of general psychiatry. 2011;​68(2):​128-137. doi:​10.1001/​archgenpsychiatry.2010.199.]])] Since then, there has been conflicting research on whether this is due to exposure to antipsychotic drugs versus the degenerative process behind psychosis.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC4264996/​|Cannon,​ Tyrone D. et al. “Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk.” Biological psychiatry 77.2 (2015): 147–157. PMC. Web. 13 Sept. 2017.]])][([[http://​journals.plos.org/​plosone/​article?​id=10.1371/​journal.pone.0101689|Veijola,​ Juha, et al. "​Longitudinal changes in total brain volume in schizophrenia:​ relation to symptom severity, cognition and antipsychotic medication."​ PLoS One 9.7 (2014): e101689.]])] In 2020, the first randomized control trial showed that antipsychotics (olanzapine specifically) changes brain structure. After 36 weeks of olanzapine exposure, individuals experienced 1.2% loss of cortical volume, which is equal to twice the yearly loss of cortical thickness in older adults.[([[https://​pubmed.ncbi.nlm.nih.gov/​32101271/​|Voineskos,​ A. N., Mulsant, B. H., Dickie, E. W., Neufeld, N. H., Rothschild, A. J., Whyte, E. M., ... & Flint, A. J. (2020). Effects of Antipsychotic Medication on Brain Structure in Patients With Major Depressive Disorder and Psychotic Features: Neuroimaging Findings in the Context of a Randomized Placebo-Controlled Clinical Trial. JAMA psychiatry.]])] However, structural MRI techniques do have inherent limitations,​ and they may not actually indicate unqualified tissue loss, and the findings from this RCT has also been challenged.[([[https://​jamanetwork.com/​journals/​jamapsychiatry/​fullarticle/​2768031|Weinberger,​ D. R., & Radulescu, E. (2020). Structural Magnetic Resonance Imaging All Over Again. JAMA psychiatry.]])] Other neuroimaging studies have also shown reductions in brain volume associated with antipsychotic uses over time.[([[https://​pubmed.ncbi.nlm.nih.gov/​34856453/​|Kanahara,​ N., Yamanaka, H., Shiko, Y., Kawasaki, Y., & Masaomi, I. (2021). The effects of cumulative antipsychotic dose on brain structures in patients with schizophrenia:​ Observational study of multiple CT scans over a long-term clinical course. Psychiatry Research: Neuroimaging,​ 111422.]])] Regardless, the results from this study should have clinicians consider the risks and benefits of antipsychotics,​ especially in patients without psychosis. Based on the research evidence of the last decade, there needs to be more urgent research on the long-term effects of antipsychotics on the brain. Interestingly,​ other studies have shown that even unaffected first-degree relatives of individuals with schizophrenia also have thinner cortical volume.[([[http://​www.pnas.org/​content/​99/​5/​3228.short|Cannon,​ Tyrone D., et al. "​Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia."​ Proceedings of the National Academy of Sciences 99.5 (2002): 3228-3233.]])] 
 + 
 +==== Mortality ​==== 
 +  ​* ​There is no significant difference in the incidence of all-cause death and death due to suicide between oral psychotics, injection antipsychotics,​ and placebo ​in individuals with schizophrenia.[([[https://​www.ncbi.nlm.nih.gov/​pmc/​articles/​PMC5049525/​|Kishi,​ T., Matsunaga, S., & Iwata, N. (2016). Mortality risk associated with long-acting injectable antipsychotics:​ a systematic review and meta-analyses of randomized controlled trials. Schizophrenia bulletin, 42(6), 1438-1445.]])] Nation-wide cohort studies have found that antipsychotic use, in particular with [[meds:​antipsychotics:​second-gen-atypical:​7-clozapine|clozapine]],​ has led to lower mortality.[([[https://​pubmed.ncbi.nlm.nih.gov/​31922669/​|Taipale,​ H., Tanskanen, A., Mehtälä, J., Vattulainen,​ P., Correll, C. U., & Tiihonen, J. (2020). 20‐year follow‐up study of physical morbidity and mortality in relationship to antipsychotic treatment in a nationwide cohort of 62,250 patients with schizophrenia (FIN20). World Psychiatry, 19(1), 61-68.]])] 
 +  * Several population-based studies have shown a risk for increased all-cause mortality in non-elderly adults with depression who are treated with second generation antipsychotic augmentation.[([[https://​pubmed.ncbi.nlm.nih.gov/​32997687/​|Gerhard,​ T., Stroup, T. S., Correll, C. U., Setoguchi, S., Strom, B. L., Huang, C., ... & Olfson, M. (2020). Mortality risk of antipsychotic augmentation for adult depression. PloS one, 15(9), e0239206.]])]
  
 ===== Resources ===== ===== Resources =====
  
 <WRAP group> <WRAP group>
-<​WRAP ​third column>+<​WRAP ​half column>
 == For Providers == == For Providers ==
   * [[http://​www.aafp.org/​afp/​2010/​0301/​p617.pdf|American Family Physician: Adverse Effects of Antipsychotic Medications]]   * [[http://​www.aafp.org/​afp/​2010/​0301/​p617.pdf|American Family Physician: Adverse Effects of Antipsychotic Medications]]
Line 189: Line 241:
   * [[https://​www.youtube.com/​watch?​time_continue=1858&​v=VZrJftfZX3I|Reconsidering Medication Discontinuation After a First Episode of Psychosis - Dr. Robert Zipursky]]   * [[https://​www.youtube.com/​watch?​time_continue=1858&​v=VZrJftfZX3I|Reconsidering Medication Discontinuation After a First Episode of Psychosis - Dr. Robert Zipursky]]
 </​WRAP>​ </​WRAP>​
-<​WRAP ​third column>​ +<​WRAP ​half column>
-== Articles == +
-  * [[https://​www.madinamerica.com/​2017/​05/​psychiatry-defends-its-antipsychotics-case-study-of-institutional-corruption/​|Mad In America - Contrarian View]] +
-</​WRAP>​ +
-<WRAP third column>+
 == Research == == Research ==
   * [[http://​www.thelancet.com/​journals/​lancet/​article/​PIIS0140-6736(16)00007-6/​references|Gould,​ I. M., & Lawes, T. (2016). Antibiotic stewardship:​ prescribing social norms. The Lancet, 387(10029), 1699-1701.]]   * [[http://​www.thelancet.com/​journals/​lancet/​article/​PIIS0140-6736(16)00007-6/​references|Gould,​ I. M., & Lawes, T. (2016). Antibiotic stewardship:​ prescribing social norms. The Lancet, 387(10029), 1699-1701.]]