antipsychotics may also cause anhedonia. drug-induced ocd main article: obsessive–compulsive disorder § drug-induced ocd many different types of medication can induce in patients that have never had symptoms before. a new chapter about ocd in the dsm-5 (2013) now specifically includes drug-induced ocd. there are reports that some atypical antipsychotics could cause drug-induced ocd in already schizophrenic patients. tardive dyskinesia all of the atypical antipsychotics warn about the possibility of tardive dyskinesia in their package inserts and in the pdr. it is not possible to truly know the risks of tardive dyskinesia when taking atypicals, because tardive dyskinesia can take many decades to develop and the atypical antipsychotics are not old enough to have been tested over a long enough period of time to determine all of the long-term risks. one hypothesis as to why atypicals have a lower risk of tardive dyskinesia is because they are much less fat-soluble than the typical antipsychotics and because they are readily released from d2 receptor and brain tissue. the typical antipsychotics remain attached to the d2 receptors and accumulate in the brain tissue which may lead to td. both typical and atypical antipsychotics can cause tardive dyskinesia. according to one study, rates are lower with the atypicals at 3.9% per year as opposed to the typicals at 5.5% per year. metabolism recently, metabolic concerns have been of grave concern to clinicians, patients and the fda. in 2003, the food and drug administration (fda) required all manufacturers of atypical antipsychotics to change their labeling to include a warning about the risks of hyperglycemia and diabetes with atypical antipsychotics. it must also be pointed out that although all atypicals must carry the warning on their labeling, some evidence shows that atypicals are not equal in their effects on weight and insulin sensitivity. the general consensus is that clozapine and olanzapine are associated with the greatest effects on weight gain and decreased insulin sensitivity, followed by risperidone and quetiapine. ziprasidone and aripiprazole are thought to have the smallest effects on weight and insulin resistance, but clinical experience with these newer agents is not as developed as that with the older agents. the mechanism of these adverse effects is not completely understood but it is believed to result from a complex interaction between a number of pharmacologic actions of these drugs. their effects on weight are believed to mostly derive from their actions on the h1 and 5-ht2c receptors, while their effects on insulin sensitivity are believed to be the result of a combination of their effects on body weight (as increased body mass is known to be a risk factor for insulin resistance) and their antagonistic effects on the m3 receptor. some of the newer agents, however, such as risperidone and its metabolite paliperidone, ziprasidone, lurasidone, aripiprazole, asenapine and iloperidone, have clinically insignificant effects on the m3 receptor and appear to carry a lower risk of insulin resistance. whereas clozapine, olanzapine and quetiapine (indirectly via its active metabolite, norquetiapine) all antagonise the m3 receptor at therapeutic-relevant concentrations. recent evidence suggests a role of the α1 adrenoceptor and 5-ht2a receptor in the metabolic effects of atypical antipsychotics. the 5-ht2a receptor, however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics. the two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole. in a meta-analysis of 18 antipsychotics, olanzapine and clozapine exhibited the worst metabolic parameters and aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone the most benign parameters. a study by sernyak and colleagues found that the prevalence of diabetes in atypical antipsychotic treatments was statistically significantly higher than that of conventional treatment. the authors of this study suggest that it is a causal relationship the kabinoff et al. suggest the findings only suggest a temporal association. kabinoff et al. suggest that there is insufficient data from large studies to demonstrate a consistent or significant difference in the risk of insulin resistance during treatment with various atypical antipsychotics. comparison table of adverse effects comparison of side effects for atypical antipsychotics generic nameweight gainmetabolic effectsepshigh prolactinsedationhypotension / orthostasisqtc prolongationanti-ach effectsother adverse effects amisulpride +++++--+++-seizures, suicidal ideation aripiprazole 0–10%0–10%10–20%-10–20%0–10%--seizures (0.1–0.3%), anxiety, rhabdomyolysis, pancreatitis (<0.1%), agranulocytosis (<1%), leukopenia, neutropenia, suicidal ideation, angioedema (0.1–1%) asenapine 0–10%20%0–10%0–10%10–20%0–10%+-immune hypersensitivity reaction, angioedema, suicidal ideation blonanserin +/--++++/--++/- clozapine 20–30%0–15%-->30%20–30%++++seizures (3–5%), agranulocytosis (1.3%), leukopenia, pneumonia, respiratory arrest, angle-closure glaucoma, eosinophilia (1%), thrombocytopenia, stevens–johnson syndrome, myocarditis, erythema multiforme and abnormal peristalsis iloperidone 0–10%0–10%0–10%-10–20%0–10%++-suicidal ideation (0.4–1.1%), syncope (0.4%) lurasidone -->30%-20–30%-++agranulocytosis, seizures (<1%), elevated serum creatinine (2–4%) melperone +++/--+/+++/++++-agranulocytosis, neutropenia and leukopenia olanzapine 20–30%0–15%20-30%20–30%>30%0–10%++acute haemorrhagic pancreatitis, immune hypersensitivity reaction, seizures (0.9%), status epilepticus, suicidal ideation (0.1–1%) paliperidone 0–10%-10–20%>30%20–30%0–10%+/- (7%)-agranulocytosis, leukopenia, priapism, dysphagia, hyperprolactinaemia, sexual dysfunction perospirone ? ?>30%+++ ?-insomnia in up to 23%, cpk elevation neuroleptic malignant syndrome quetiapine 20–30%0–15%10–20%->30%0–10%+++agranulocytosis, leukopenia, neutropenia (0.3%), anaphylaxis, seizures (0.05–0.5%), priapism, tardive dyskinesia (0.1–5%), suicidal ideation, pancreatitis, syncope (0.3–1%) remoxipride +/-----+/- ?-there is a risk of aplastic anaemia risk which is what led to its removal from the market. risperidone 10–20%0–10%20–30%>30%>30%0–10%+-syncope (1%), pancreatitis, hypothermia, agranulocytosis, leukopenia, neutropenia, thrombocytopenia, hyperprolactinaemia, sexual dysfunction, thrombotic thrombocytopenic purpura, cerebrovascular incident (<5%), tardive dyskinesia (<5%), priapism, neuroleptic malignant syndrome (<1%), gynecomastia, galactorrhea sertindole +++/--++-++++++-- sulpiride ++++++-++++-jaundice ziprasidone 0–10%0–10%0–10%-20–30%0–10%++-syncope (0.6%), dysphagia (0.1–2%), bone marrow suppression, seizure (0.4%), priapism discontinuation the british national formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. other symptoms may include restlessness, increased sweating, and trouble sleeping. less commonly there may be a feeling of the world spinning, numbness, or muscle pains. symptoms generally resolve after a short period of time. there is tentative evidence that discontinuation of antipsychotics can result in psychosis. it may also result in reoccurrence of the condition that is being treated. rarely tardive dyskinesia can occur when the medication is stopped. pharmacology pharmacodynamics the atypical antipsychotics integrate with the serotonin (5-ht), norepinephrine (α, β), and dopamine (da) receptors in order to effectively treat schizophrenia. d2 receptor: hyperactive dopaminergic activity on d2 receptors in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). after taking an antipsychotic, antagonism of d2 receptors occurs throughout the entire brain, leading to a number of deleterious side effects from d2 receptor antagonism throughout the entire dopamine pathway system. it's not possible to affect d2 receptors only in the mesolimbic pathway, but 5-ht2a receptor antagonism reverses these side effects to some extent. reducing d2 dopaminergic activity in the mesolimbic pathway also results in an anhedonic effect, reducing pleasure and motivation. in the mesocortical pathway to the dlpfc and vmpfc, endogenous d2 receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. d2 receptor antagonism further compounds these problems. in the nigrostriatal pathway, d2 receptor antagonism results in extrapyramidal symptoms. if this antagonism occurs long enough, symptoms of eps may become permanent, even if antipsychotic use is discontinued. in the tuberoinfundibular pathway, d2 receptor antagonism results in elevated prolactin. if prolactin levels become high enough, hyperprolactinaemia may occur, resulting in sexual dysfunction, weight gain, more rapid demineralization of bones, and possibly galactorrhea and amenorrhea. 5-ht2a receptor: when serotonin is released on to postsynaptic 5-ht2a receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. this brake is disrupted through action of a 5-ht2a antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. the result of this is that dopamine competes with antipsychotic d2 antagonistic action at d2 receptors, thereby reducing antagonistic binding there and eliminating or lowering d2 antagonistic effects in several pathways of the dopamine system. in the nigrostratial pathway, it reduces eps. in the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. dopamine release in the mesolimbic pathway from 5-ht2a antagonism does not appear to be as robust as in the other pathways of the dopamine system, thereby accounting for why atypical antipsychotics still retain part of their efficacy against the positive symptoms of schizophrenia through their d2 antagonism. when 5-ht2a antagonistic agent particles occupy 5-ht2a receptors in the mesocortical pathway and in the prefrontal cortex, the negative symptoms of schizophrenia, affective symptoms, and cognitive deficits and abnormalities are treated and reduced. furthermore, 5-ht2a receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing glutamate release, which in turn lowers hyperactive dopaminergic d2 receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia. brexpiprazole, approved by the us fda in 2015, has a similar binding profile to aripiprazole as a partial d2 agonist with moderate histamine binding, but with brexipiprazole has a higher affinity for serotonin receptor 5-ht2a some effects of 5-ht1a receptor activation include decreased aggressive behavior/ideation, increased sociability, and decreased anxiety and depression. blockade of the 5-ht2c receptor increases serotonin, releasing norepinephrine and dopamine within the brain. but neuronal reuptake of norepinephrine is limited sharply by some antipsychotics, e.g. ziprasidone. increased norepinephrine can cause increased glucose(blood sugar) levels. increased blood sugar levels by increased norepinephrine causes hunger in many humans, which is why weight gain occurs with some antipsychotics if the norepinephrine is not inhibited. inhibition of norepinephrine stabilizes mood in humans. 5-ht6 receptor antagonists improve cognition, learning, and memory. the 5-ht7 receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. the antipsychotics asenapine, lurasidone, risperidone, and aripiprazole are very potent at the 5-ht7 receptor. antagonistic affinity for the h1 receptor also has an antidepressant effect. h1 antagonism blocks serotonin and norepinephrine reuptake. patients with increased histamine levels have been observed to have lower serotonin levels. however, the h1 receptor is linked to weight gain. to have partial agonism at the 5-ht1a receptor can yield absence of weight gain in an antipsychotic. this is very relevant for ziprasidone, but it creates a risk for a prolonged qtc interval. on the other hand, blockade of the 5-ht3 receptor removes the risk for a prolonged qtc interval, but then creates a larger risk for weight gain. relation to the 5-ht3 receptor increases caloric uptake and glucose, which is seen in clozapine and olanzapine. other ways for dopamine to resolve is to have agonism at both the d2 receptor and 5-ht1a receptor, which normalizes the dopamine level in the brain. this occurs with cariprazine and aripiprazole. whether the anhedonic, loss of pleasure and motivation effect resulting from dopamine insufficiency or blockade at d2 receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-ht2a antagonism, which is seen in atypical antipsychotics), or the positive mood, mood stabilization, and cognitive improvement effect resulting from atypical antipsychotic serotonergic activity is greater for the overall quality of life effect of an atypical antipsychotic is a question that is variable between individual experience and the atypical antipsychotic(s) being used. terms inhibition. disinhibition: the opposite process of inhibition, the turning on of a biological function. release: causes the appropriate neurotransmitters to be discharged in vesicles into the synapse where they attempt to bind to and activate a receptor. downregulation and upregulation. binding profile note: unless otherwise specified, the drugs below serve as antagonists/inverse agonists at the receptors listed. generic named1d2d3d45-ht1a5-ht1b5-ht2a5-ht2c5-ht65-ht7 α1aα1α2m1m3h1 amisulpride-++++++++------++/+ -+/---- aripiprazole+++++ (pa)+++ (pa)+ (pa)+++ (pa)++++++ (pa)++++ (pa) ++/++--++/+ asenapine++++++++++++++++ (pa)+++++++++++++++++++ ++++++--+++ blonanserin-+++++++++- ?++++++/- + (rc)+ (rc)+ ?- brexpiprazole+++++++ (pa)++++ (pa)+++++++++ (pa)+++++++++++ (pa)+++++++ ++-+++ cariprazine++++ (pa)+++++ (pa)++++ (pa)+++++++ ++--+++ clozapine+++++++++++ (pa)++/+++++++++++++++ ++++++++++++++++++ iloperidone++++++++++ (pa)++++++++ +++++++/++--+++ lurasidone++++++++++++ (pa) ?+++++/- ?++++ -+++/++--- melperone ?+++++++++ (pa) ?+++-++ ++++--++ olanzapine+++++++++++++ (pa)++++++++++++++ ++++++++++++++++ paliperidone+++++++++++ (pa)+++/+++++++-++++/+++ ++++++--+++/++ quetiapine+++/+++/++++/+ (pa)++++++++/++ +++++++/+++++++++++ risperidone+++++++++++ (pa)++++++++-+++/++ +++++/++++--++ sertindole ?+++++++++++/+ (pa)+++++++++++++++ ++++/++++--++/+ sulpiride ?+++++++++++------ ----- ziprasidone+++/+++++++++++/+++++ (pa)+++ (pa)+++++++(pa)+++++ +++/++++--++ zotepine+++/+++++++++/++++++++ (pa)+++++++++++ (rc)++++++++/+++ ++++++/++++ (rc)++ (rc)++++ legend: no affinity or no data -clinically insignificant +low ++moderate +++high ++++very high +++++exceptionally high papartial agonist rccloned rat receptor pharmacokinetics atypical antipsychotics are most commonly administered orally. antipsychotics can also be injected, but this method is not as common. they are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood–brain barrier and placental barriers. once in the brain, the antipsychotics work at the synapse by binding to the receptor. antipsychotics are completely metabolized in the body and the metabolites are excreted in urine. these drugs have relatively long half-lives. each drug has a different half-life,