- Introduction to antipsychotics (700 words)– look at my chapter, how antipsychotics works in the brain, how they all work. OVERALL, differences between first and second generation antipsychotics, overall side effect profiles (second generation – metabolic adrs, first generation more movement disorders, various movement disorders, what happens when there’s deficiency in dopamine etc).
The genesis of contemporary psychopharmacology originated in the late 1940s and early 1950s. During this period, several drugs were discovered that benefited psychiatric disorders. The discovery of some of these earlier psychotropic medications was serendipitous in nature, in that many of the agents after being used for some time for other medical indications had “adverse effects” that actually relieved symptoms of severe psychiatric illnesses.
Chlorpromazine is the most notable example of a psychiatric medication discovered by chance. A phenothiazine compound, chlorpromazine, helped relieve symptoms of mania and psychosis in the 1950s. However, prior to their introduction as an antipsychotic, phenothiazines as a class had long been utilized for other indications. For example, in 1891, Paul Ehrlich learned of the antimalarial effects of a phenothiazine derivative called methylene blue. Also, promethazine, a phenothiazine, was synthesized in 1940s and developed for its antihistaminergic properties. In 1951, Laborit and Huguenard administered chlorpromazine to patients for its potential anesthetic property as an adjunctive medication for surgery. Soon thereafter in 1952, multiple groups began to publish reports suggesting chlorpromazine was an effective treatment for psychotic patients. In 1952 chlorpromazine became available in France with worldwide use beginning in 1953. The introduction of chlorpromazine for the treatment of mania and psychosis in the 1950s precipitated the psychopharmacological revolution. Between 1954 and 1975, around 40 antipsychotic drugs were introduced throughout the world and about 15 antipsychotic medications were introduced in the United States (US). Following this period there was a gap in the development of antipsychotic agents until the introduction of clozapine in the US in 1990 that led to the development of a the second generation antipsychotic drug class. The second generation antipsychotic medications claimed to be “atypical antipsychotics” due to their lower risk of movement problems, such as extrapyramidal symptoms (EPS), more commonly observed with the typical antipsychotics, and an increased efficacy for the negative symptoms of schizophrenia compared to typical antipsychotics. However, these advantages were partially offset by an increased incidence of metabolic adverse effects resulting in significant weight gain leading to diabetes and cardiovascular disease adverse effects for some but not all of these new second generation antipsychotic compounds.
As discussed earlier, chlorpromazine gained popularity initially for its antihistaminic effects. However, its therapeutic actions in addressing psychosis in patients with schizophrenia are not mediated by this property, but by its D2 receptor blockade. The first generation antipsychotic agents, known for their D2 antagonism, such as chlorpromazine, are also referred to as typical antipsychotics, conventional antipsychotics or neuroleptics. The neurolepsis that result from the use of these agents translates clinically to a combination of decreased motor movements and increased slowness. Neuroleptics are able to compete at several receptor sites, but clinical potency of the average typical antipsychotic correlates closely only with the drug affinity for DA receptors. Therefore, the D2 receptor antagonism not only contributes to clinical effects but is responsible for some of the side effects, most notably the neurolepsis.
More specifically, D2 antagonism in various parts of the brain can lead to different clinical effects. To further understand these actions, the four DA pathways of the brain should first be explained. The four DA pathways, as implied in antipsychotic therapy, are (1) the mesolimbic pathway, (2) the mesocortical pathway, (3) the tuberoinfundibular pathway and (4) the nigrostriatal pathway. Antagonism of D2 receptors in the mesolimbic pathway is associated with decreased positive symptoms of schizophrenia such as delusions, hallucinations and racing thoughts. The D2 blockade in the mesocortical pathway contributes to the negative symptoms of schizophrenia such as apathy, lack of emotion, and poor or non-existent social functioning. Additionally, D2 blockade in the nigrostriatal pathway mediates the movement problems such extrapyramidal symptoms (EPS) that are generally experienced with antipsychotics, more so with the typical antipsychotic class. If the D2 receptors in the nigrostriatal DA pathway are blocked overtime chronically, this can lead to a hyperkinetic movement disorder known as tardive dyskinesia (TD). TD causes facial and tongue movements such as chewing, tongue protrusions, and facial grimacing, as well as limb movements, which can be quick, jerky or choreiform. Finally, the tuberoinfundibular pathway mediates hyperprolactinemia, yet another side effect from the use of antipsychotic agents. In addition to their effect on the D2 receptor, the first generation antipsychotics also block the muscarinic cholinergic receptors (M1), the alpha-1 adrenergic receptors (alpha 1), and the histamine receptors (H1). Table 1 further elaborates on dopamine and serotonin receptor subtypes implicated in schizophrenia treatment.
The first generation antipsychotic class dominated the drug market until the introduction of clozapine, the first second generation antipsychotic agent, in the 1972 in Switzerland and Austria but not approved in the U.S. until 2002. Shortly after, a number of second generation antipsychotics were granted FDA approval. The second generation antipsychotics not only block the D2 receptors, similar to typical agents, but also block the 5-HT2A receptor. In the nigrostriatal pathway, 5-HT inhibits DA release at the level of DA cell bodies in the brainstem substantia nigra and also at the axon terminals. Therefore, since 5-HT2A receptor stimulation results in inhibition of DA release, 5-HT2A antagonism in the nigrostriatal pathway leads to lower risk of movement problems. The same is true for the mesocortical DA pathway. The blockade of 5-HT2A receptors with a second generation antipsychotic also leads to DA release, leading to compensation for the DA deficiency and improvements in negative symptoms. Clinically, this results in lower EPS as well as better efficacy for negative symptoms of schizophrenia. Moreover, first generation antipsychotics are not efficacious against the negative symptoms of schizophrenia and may even worsen them.[7, 8]
Though second generation antipsychotic medications have become the most widely used class of medications to treat psychoses due of safety and tolerability profile compared to first generation antipsychotics, they are not free from side effects. Second generation antipsychotics as a class are associated with a greater risk of metabolic side effect profile such as weight gain, lipid imbalances, as well as glycemic dysregulation and risk of diabetes mellitus and diabetic ketoacidosis. Due to these risks, American Diabetes Associations recommends careful baseline and periodic monitoring for metabolic side effects. Each agent within the second generation antipsychotic class differs in severity of metabolic side effects and some agents are associated with additional side effects. For example, patients taking clozapine require ongoing monitoring because of the risk of serious blood dyscrasias, especially agranulocytosis.
- Include the receptors the drugs bind to and potency.
- Indications (200 words)- include all indications, even off label (schizophrenia, schizoaffective, adjunct to depression, bipolar (mania/maintenance/depression), agitation, psychosis, autism related disorders, hiccups, etc). Why do we think its used for hiccups (find refs).
Antipsychotics are used for various disease states. Psychosis patients such as schizophrenic patients are commonly treated with atypical antipsychotics.  Atypical antipsychotics have less adverse effects, which helps with patient adherence . However, there are times were some patients experience no relieve from schizophrenia with antipsychotics. There are certain antipsychotics used in treatment-resistant schizophrenia such as Clozapine.  Interestingly antipsychotics may be used in cases that seem unusual. For instance, in cases of persistent hiccups patients may be prescribed chlorpromazine.  Chlorpromazine is the only antipsychotic FDA approved drug for hiccups.  Autism awareness in spreading quickly and has been helping with autism research.  Aripiprazole is commonly used in autism and is FDA approved.  Aripiprazole has shown to reduce autism symptoms such as irritability and aggression.  Certain antipsychotics may be used in treatment of nausea and vomiting. In a randomized double-blind trial, chlorpromazine was compared to placebo and droperidol.  The group of patients being tested were ovarian cancer patients receiving cisplatin.  The study showed chlorpromazine reduced nausea and vomiting in both groups. 
- Prolonged QT
QT wave is a measurement of the depolarization and repolarization of the heart’s ventricles.  QT prolongation can be fatal if not monitored. Many drugs can prolong QT, so it is extremely crucial that healthcare providers monitor patients on drugs that have the potential to increase QT. Normal values for QT differ in males and females; QTc >450 msec for males and >470 msec in females is considered prolonged. QT prolongation is when ventricular repolarization is much more extensive, which causes early afterdepolarization (EAD). [12-16] This phenomenon can lead to Torsade de Pointes or other arrhythmias such as ventricular fibrillation. [12-16]
There are several medications that prolong QT intervals and it is important to do a drug-drug interaction and to be aware of those drug classes. For instance, some antiarrhythmic, antibiotics, antiemetics, antidepressants, and antipsychotics can prolong QT intervals.  Patients with Schizophrenia have lower life expectancy than others because of several reasons and one reason is due to the use of antipsychotic drugs which cause cardiovascular disease.  As mentioned previously, first generation antipsychotics have many adverse effects; therefore, they are not used as commonly. One of their side effects is prolonging QT interval and out of all typical antipsychotics Chlorpromazine, Levomepromazine and IV haloperidol prolonged QT the most . Also, all other antipsychotics increase QT interval such as Ziprasidone, Thioridazine, and Aripiprazole.  Many of these antipsychotic drugs are dose dependent when it comes to prolonging QT intervals.  Other antipsychotic drugs may cause an increase in QT but may not be as high risk as previously mentioned. It is important to take caution and monitor QT intervals with antipsychotic drugs and even more if given in combination with other drugs.
- Metabolic Changes
Metabolic syndrome occurs when psych patients are on antipsychotic medication chronically.  These changes include weight gain, increase in lipid levels, and increase in glucose level in the bloodstream, which increases the risk of diabetes.  However, not everyone on antipsychotics develops metabolic syndrome.  Metabolic changes can increase the risk of cardiovascular issues.  Heart disease is significant in schizophrenic patients and it accounts for high rates of mortality.  Hyperlipidemia can pose many other risk factors such cardiovascular issues. Prior to starting antipsychotics it is recommended that patients have labs drawn at baseline to check for lipid and glucose levels.  Atypical antipsychotics such as clozapine, quetiapine, and olanzapine increase lipid levels more than ziprasidone, risperidone, and aripiprazole. 
- Glucose ADA 2014 guidelines monitoring for atypical antipsychotics– look at table and include in this section what to monitor
High levels of glucose in the blood can be dangerous due to increasing the risk of ketoacidosis.  Diabetes usually occurs a few months after initiation of antipsychotics.  Studies have shown clozapine and olanzapine cause the most increase in glucose levels. [25, 26] Also, another study conducted by Newcomer et al. compared clozapine, olanzapine, and risperidone.  In this study, clozapine and olanzapine causes the most increase in blood glucose.  Risperidone, when compared to olanzapine and clozapine showed no difference in blood glucose levels.  Another study by Sernyak et al. was conducted which compared typical and atypical antipsychotics to see which drugs increase the risk of diabetes.  The drugs that were included were typical antipsychotics and atypical antipsychotics such as clozapine, risperidone, quetiapine, or olanzapine.  Risk of diabetes was higher in clozapine, olanzapine, and quetiapine group versus typical antipsychotics or risperidone. 
- Weight gain
Weight gain can be uncomfortable for patients. It can also put patients at risk of other health issues.  Atypical antipsychotics have shown to increase the risk of weight gain.  Per ADA guidelines, patients on SGA should be monitored for weight, personal/family history, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile at baseline. (ADA guidelines http://care.diabetesjournals.org/content/27/2/596#T1) In a randomized double blinded study clozapine and haloperidol were compared for weight gain. At the end of the trial, more patients in the clozapine group had gained weight.  Another retrospective was conducted by Wirshing and colleagues , comparing Haloperidol to atypical antipsychotics such as risperidone, clozapine, olanzapine, and sertindole.  Clozapine and olanzapine treatment group had the most weight gain out of all groups.  Second after clozapine and olanzapine were patients treated with risperidone.  The least weight gain was in the haloperidol group.  CATIE trial showed olanzapine being a favorable and effective drug, but drug has high risk of metabolic syndrome which can make it less favorable. 
Neuroleptic malignant syndrome is a rare adverse effect associated with the use of antipsychotics.  Symptoms of neuroleptic malignant syndrome include “hyperpyrexia, muscle rigidity, autonomic dysfunction and altered mental status”.  NMS usually occurs due to the blockage of the dopamine receptor.  Although many adverse effects are seen with typical antipsychotics, neuroleptic malignant syndrome is seen in both highly potent typical antipsychotics and atypical antipsychotics.  Highly potent first generation antipsychotics such as haloperidol, chlorpromazine and fluphenazine are associated with NMS.  In a case report conducted by Troller et al, it was shown that atypical antipsychotic, most commonly Clozapine has more neuroleptic malignant syndrome side effect than first generation antipsychotics, but there were reports of NMS in other atypical antipsychotics.  Other atypical drugs that can cause NMS are quetiapine , olanzapine , aripiprazole , and risperidone. 
Even though NMS is rare, it is extremely crucial for providers to know how to manage and be able to provider pharmacological care. First and foremost, drug that is causing NMS must be discontinued.  Patients with NMS are normally dehydrated so it is important to give fluids and prevent electrolyte imbalance.  If the first few steps were not sufficient then medical management is needed.  It is difficult to determine which agents are used as first line as there are not sufficient clinical trials to determine which drug is superior. Drugs that are commonly used are benzodiazepines, dantrolene, and dopaminergic agents such as amantadine and bromocriptine.  Benzodiazepines are used in milder cases and they do not prevent NMS if used in conjunction with agents that cause NMS.  Most common benzodiazepine that is used is Lorazepam IV, which has been used in more acute setting and has shown benefit.  In more extreme cases, muscle relaxants such as dantrolene can be used; however, because of its risk of hepatotoxicity clinicians should stop dantrolene once symptoms are resolved. 
Antipsychotics have a variety of side effect and some are mentioned in this chapter. One of the alarming side effects is a movement disorder that most commonly occur in FGA. Movement disorders can be distressing for patients as it can cause non-adherence and increase their psychotic behaviors.  Second generation antipsychotics are less likely to cause extrapyramidal symptoms.  Dystonia is a neurologic disorder which causes overactive movements.  The movement can be slow or jerky. [41, 42] Dystonia has different levels of extremes. In cases with moderate dystonia, the patient has more constricted and rigid movements.  In severe cases patients have more obvious deformities.  There are different factors that can increase a patient’s risk of developing dystonia such as age, being a male, and drug abuse such as Cocaine. [43-48]
Drug-induced Dystonia is due to the mechanism of action of these drugs, which is the blockage of D2 receptors.  If the blockage is stronger then there is a higher chance of Dystonia side effects and examples of those drugs are haloperidol, fluphenazine, and pimozide.  “Atypical drugs such as olanzapine, quetiapine, sertindole, and lower doses of risperidone are less likely to cause Dystonia”.  However, clozapine is the only drug that does not cause dystonia in the SGA.  Dystonia is usually treatable with dopamine related drugs such as Levadopa. Levadopa for the treatment of dystonia should be administered in lower doses, and should be titrated up slowly to get effective response.  Another class of drugs that are commonly prescribed are benzodiazepines.  Muscle relaxants are also prescribed to help decrease the muscle activity; however, not much studies have been done on their use for dystonia.  Also, Botulinum Neurotoxins are used in dystonia as they paralyze the muscle, which helps prevent the vigorous movement of muscle.  Botulinum Neurotoxins are recommended as a first line for treatment of “blepharospasm, cervical dystonia, oromandibular and laryngeal dystonia”.  These are some of the common classes of drugs that are used in the treatment of dystonia.
Akathisia mostly occurs in the limbs with motor restlessness and a sense of agitation.  It may have similar symptoms to parkinsonism, which can lead to poor medication adherence.  Some studies have shown that Akathisia can potentially increase the risk of tardive dyskinesia in young adults and the elderly.  Symptoms of akathisia include, “rocking from foot to foot, shuffling of legs, or swinging one leg over the other while sitting”.  In severe cases of akathisia, patients have a hard time being in any position such as “sitting, lying, or standing” 
Many reports have shown that drug-induced akathisia is dose dependent; therefore, it is recommended to start at a lower dose and increase dose slowly.  Similar to dystonia, akathisia is mostly common in FGA rather than SGA.  In order to prevent akathisia it is recommended to use SGA over FGA.  Although the mechanism of akathisia is not clear there are hypothesis that dopamine receptors are blocked in other “areas of the brain rather than the striatum”.  Treatment of akathisia is interesting but promising. Beta blockers have shown great efficacy as they pass the blood brain barrier and block D2 receptors.  Studies have shown the efficacy of propranolol in reversing akathisia and its superiority to other drugs such as amantadine, benztropine, and benzodiazepines.[54, 55] Benzodiazepines are shown to be effective in treating acute and chronic akathisia. [56-58] Studies have shown that Lorazepam was inferior to propranolol and clonazepam helps with reducing the symptoms of akathisia. [52, 57]
- Tardive dyskinesia- valbanism/Ingreza used for treatment
Tardive dyskinesia has a later onset than the other movement disorders.  The cause of tardive dyskinesia is similar to all other movement disorders due to dopamine receptor blockage.  Tardive dyskinesia affects the motor system; however, what distinguishes tardive dyskinesia from other movement disorders is its unique feature of affecting the tongue and mouth.  FGA are more likely to cause tardive dyskinesia SGA due to the high affinity the FGA drugs have for dopamine receptors. [59, 60] SGA such as risperidone, olanzapine, quetiapine, amisulpride, and ziprasidone are less likely to cause tardive dyskinesia.  Some risk factors of tardive dyskinesia are: “age, gender specifically females, African American, brain damage, pre-existing movement disorder, and drug abuse”. [62-64]
Providers should be aware of which drug classes can causes tardive dyskinesia for preventative measures. In order to treat tardive dyskinesia, the discontinuation of the drug that is causing it should be the first step providers should take.  Most of these patients are on these medications chronically; however, in the case of antipsychotics patients can switch to atypical antipsychotics even though they still have the risk of developing tardive dyskinesia with these drugs there is a lower chance of development.  Studies have shown that clozapine and quetiapine are efficacious in reducing tardive dyskinesia symptoms; however, these drugs must be given in high doses.  Other drugs classes such as dopamine-depleting drugs also known as vesicular monoamine transporter 2 inhibitors have been efficacious in treating tardive dyskinesia.  Terabenazine is used as first line in managing tardive dyskinesia symptoms.  A new drug has recently emerged call Valbenazine, which is in the same class as Terabenazine. Velbenazine has shown to be efficacious alleviating tardive dyskinesia symptoms in a “phase 2 randomized, double blind, placebo-controlled study”. (Guy W). Velbenazine was approved on April 11, 2017 (FDA.gove) because it is a new drug so it is hard to say if its preferred over Terabenazine (I didn’t get this from anywhere, just assuming). Other drugs may be used such as “benzodiazepines, baclofen, valproic acid [67-70], donepezil , lithium , antioxidants [67, 73], zonisamide , vitamin B6 , melatonin , zolpidem ”; however, there is not enough data to support the use of these medications, but smaller studies and case reports have shown benefits of these drugs. 
Similar to other movement disorders, pseudoparkinsonism is due to blockade of dopamine receptors.  Pseudoparkinsonism usually occurs a few day to weeks upon initiation of antipsychotics.  The symptoms are similar to Parkinson’s disease so it can be difficult to clinically distinguish between drug induced parkinsonism and Parkinson disease.  Many times clinicians prescribe antiparkinsonian medication when the cause of the tremor is due to medications.  A Study has shown typical antipsychotics such as chlorpromazine cause pseudoparkinsonism in 40% of their patient population.  One common risk factor of pseudoparkinsonism is age since there’s a decrease in dopamine in the brain.  [88-90] Also, another risk factor is being female since estrogen can decrease the levels of dopamine being released. [91-95]
Drugs that are shown to increase the risk of pseudoparkinsonism are typical antipsychotics such as chlorpromazine, promazine, haloperidol, perphenazine, fluphenazine, pimozide.  Atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine, and aripiprazole still have the risk of causing pseudoparkinsonism.  Because of their fast dissociation from dopamine receptor decreases movement disorders. [97, 98] Clozapine is the only atypical antipsychotic that does not cause pseudo parkinsonism ; however, due to its agranulocytosis side effect its is not a first line drug.  Drug-induced pseudoparkinsonism can be treated by discontinuing by causative drug, which would reverse symptoms. 
- Hematologic system
Studies have shown patients on antipsychotic drugs are at risk of hematologic changes. Neutropenia and agranulocytosis are the most common hematologic side effects. (R.J. Baldessarini). Patients starting on psychotropic medication should be monitored closely the first few months for any signs of hematologic disorders since hematologic problems arise in the beginning, and agranulocytosis within 21 to 28 days of starting psychotropics.  Neutropenia is defined when neutrophils are less than 1,500/mm3 (RP kealing) and Agranulocytosis is when the bone marrow stops producing granulocytes and puts the body at risk of infections. 
Both FGA and SGA can cause hematologic changes. Clozapine can cause agranulocytosis which requires monitoring prior to initiation of drug and during the course of the medication.  Patient on Clozapine must have there CBCs monitored weekly.  Clozapine should be discontinued if WBC is less than 2,000/mm3 or ANC less than 1,000/mm3, however, if WBC is less than 1,500/mm3 or ANC </= 1,500/mm3 then Clozapine should never be restarted. 
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