Kindling can cause complications and may increase the risk of relapse,  alcohol-related brain damage  and cognitive deficits. Chronic alcohol misuse and kindling via multiple alcohol withdrawals may lead to permanent alterations in the GABA A  receptors. [ 27 ]  The mechanism behind kindling is sensitization of some neuronal systems and desensitization of other neuronal systems which leads to increasingly gross neurochemical imbalances. This in turn leads to more profound withdrawal symptoms including  anxiety ,  convulsions  and  neurotoxicity . [ 26 ]


Binge drinking is associated with increased impulsivity, impairments in  spatial working memory  and impaired  emotional learning . These adverse effects are believed to be due to the neurotoxic effects of repeated withdrawal from alcohol on aberrant neuronal plasticity and cortical damage. Repeated periods of acute intoxication followed by acute detoxification has profound effects on the brain and is associated with an increased risk of seizures as well as cognitive deficits. The effects on the brain are similar to those seen in alcoholics who have detoxified repeatedly but not as severe as in alcoholics who have no history of prior detox. Thus, the acute withdrawal syndrome appears to be the most important factor in causing damage or impairment to brain function. The brain regions most sensitive to harm from binge drinking are the  amygdala  and  prefrontal cortex . [ 28 ]


People in adolescence who experience repeated withdrawals from  binge drinking  show impairments of long-term nonverbal memory. Alcoholics who have had two or more alcohol withdrawals show more frontal lobe cognitive dysfunction than those who have experienced one or no prior withdrawals. Kindling of neurons is the proposed cause of withdrawal-related cognitive damage. Kindling from repeated withdrawals leads to accumulating neuroadaptive changes. Kindling may also be the reason for cognitive damage seen in binge drinkers. [ 29 ]


Many hospitals use the  Clinical Institute Withdrawal Assessment for Alcohol  (CIWA) protocol in order to assess the level of withdrawal present and therefore the amount of medication needed. [ 12 ]  When overuse of alcohol is suspected but drinking history is unclear, testing for elevated values of carbohydrate-deficient transferrin or gammaglutamyl transferase can help make the diagnosis of alcohol overuse and dependence more clear. The CIWA has also been shortened (now called the CIWA-Ar), while retaining its validity and reliability, to help assess patients more efficiently due to the life-threatening nature of alcohol withdrawal. [ 30 ]


Benzodiazepines   are effective for the management of symptoms as well as the prevention of seizures. [ 31 ]  Certain vitamins are also an important part of the management of alcohol withdrawal syndrome. In those with severe symptoms inpatient care is often required. [ 11 ]  In those with lesser symptoms treatment at home may be possible with daily visits with a health care provider. [ 11 ]


Cohort studies  have demonstrated that the combination of  anticonvulsants  and  benzodiazepines  is more effective than other treatments in reducing alcohol withdrawal scores and shortening the duration of  intensive care unit  stays. [ 32 ]


Benzodiazepines are the most commonly used medication for the treatment of alcohol withdrawal and are generally safe and effective in suppressing symptoms of alcohol withdrawal. [ 33 ]  This class of medication is generally effective in symptoms control, but needs to be used carefully. Although benzodiazepines have a long history of successfully treating and preventing withdrawal, there is no consensus on the ideal one to use. The most commonly used agents are long-acting benzodiazepines, such as  chlordiazepoxide  and  diazepam . These are believed to be superior to other benzodiazepines for treatment of delirium and allow for longer periods between doses. However, benzodiazepines with intermediate half-lives like  lorazepam  may be safer in people with liver problems. [ 34 ]  Benzodiazepines showed a protective benefit against alcohol withdrawal symptoms, in particular seizure, compared to other common methods of treatment. [ 35 ]


The primary debate between use of long-acting benzodiazepines and short-acting is that of ease of use. Longer-acting drugs, such as diazepam, can be administered less frequently. However, evidence does exist that "symptom-triggered regimens" such as those used when treating with lorazepam, are as safe and effective, but have decreased treatment duration and medication quantity used. [ 34 ]


Although benzodiazepines are very effective at treating alcohol withdrawal, they should be carefully used. Benzodiazepines should only be used for brief periods in alcoholics who are not already dependent on them, as they share cross tolerance with alcohol. There is a risk of replacing an alcohol addiction with benzodiazepine dependence or adding another addiction. Furthermore, disrupted GABA benzodiazepine receptor function is part of  alcohol dependence  and chronic benzodiazepines may prevent full recovery from alcohol induced mental effects. [ 36 ] [ 37 ]  The combination of benzodiazepines and alcohol can amplify the adverse psychological effects of each other causing enhanced depressive effects on mood and increase suicidal actions and are generally contraindicated except for alcohol withdrawal. [ 38 ]


Alcoholics are often deficient in various nutrients, which can cause severe complications during alcohol withdrawal, such as the development of  Wernicke syndrome . To help to prevent Wernicke syndrome, these individuals should be administered a multivitamin preparation with sufficient quantities of thiamine and folic acid. During alcohol withdrawal, the prophylactic administration of  thiamine ,  folic acid , and  pyridoxine  intravenously is recommended before starting any carbohydrate-containing fluids or food. These vitamins are often combined into a  banana bag  for intravenous administration. [ 39 ]


Very limited evidence indicates that  topiramate  or  pregabalin  may be useful in the treatment of alcohol withdrawal syndrome. [ 40 ]  Limited evidence supports the use of  gabapentin  or  carbamazepine  for the treatment of mild or moderate alcohol withdrawal as the sole treatment or as combination therapy with other medications; however, gabapentin does not appear to be effective for treatment of severe alcohol withdrawal and is therefore not recommended for use in this setting. [ 40 ] [ 41 ]  A 2010  Cochrane review  similarly reported that the evidence to support the role of anticonvulsants over benzodiazepines in the treatment of alcohol withdrawal is not supported. [ 42 ]   Paraldehyde  combined with  chloral hydrate  showed superiority over chlordiazepoxide with regard to life-threatening side effects and carbamazepine may have advantages for certain symptoms. [ 42 ]  Long term anticonvulsant medications are not usually recommended in those who have had prior seizures due to withdrawal. [ 43 ]


There are three medications used to help prevent a return to drinking:  naltrexone ,  acamprosate , and  disulfiram . They are used after withdrawal has occurred. [ 44 ]


Clonidine  may be used in combination with benzodiazepines to help some of the symptoms. [ 12 ]  No conclusions can be drawn concerning the efficacy or safety of  baclofen  for alcohol withdrawal syndrome due to the insufficiency and low quality of the evidence. [ 45 ]


Antipsychotics , such as  haloperidol , are sometimes used in addition to benzodiazepines to control agitation or psychosis. [ 12 ]  Antipsychotics may potentially worsen alcohol withdrawal as they lower the seizure threshold.  Clozapine ,  olanzapine , or low-potency  phenothiazines  (such as  chlorpromazine ) are particularly risky; if used, extreme caution is required. [ 46 ]


While intravenous  ethanol  could theoretically be used, evidence to support this use, at least in those who are very sick, is insufficient. [ 47 ]


Hypertension is common, and some doctors also prescribe beta blockers during withdrawal.


Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death. [ 48 ]  It has been proposed that brain damage due to alcohol withdrawal may be prevented by the administration of  NMDA antagonists ,  calcium antagonists , and  glucocorticoid antagonists . [ 49 ]


Continued use of benzodiazepines may impair recovery from psychomotor and cognitive impairments from alcohol. [ 50 ]  Cigarette smoking may slow down or interfere with recovery of brain pathways in recovering alcoholics. [ 51 ]


The  atypical antipsychotics  ( AAP ), also known as  second generation antipsychotics  ( SGAs ) and  serotonin –dopamine antagonists  ( SDAs ), [ 1 ] [ 2 ]  are a group of  antipsychotic  drugs (antipsychotic drugs in general are also known as  tranquilizers  and  neuroleptics , although the latter is usually reserved for the  typical antipsychotics ) largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval (e.g. by the  FDA  of the  US , the  TGA  of  Australia , the  MHRA  of the  UK ) for  schizophrenia ,  bipolar disorder , irritability in  autism , and as an  adjunct  in  major depressive disorder .


Both generations of medication tend to block receptors in the brain's  dopamine pathways . Atypicals are less likely than  haloperidol —the most widely used  typical antipsychotic —to cause  extrapyramidal   motor control   disabilities  in patients such as unsteady  Parkinson's disease –type movements, body  rigidity , and involuntary  tremors . However, only a few of the atypicals have been demonstrated to be superior to lesser-used, low- potency  first-generation antipsychotics in this regard. [ 3 ] [ 4 ] [ 5 ]


As experience with these agents has grown, several studies have questioned the utility of broadly characterizing antipsychotic drugs as "atypical/second generation" as opposed to "first generation", noting that each agent has its own efficacy and side-effect profile. It has been argued that a more nuanced view in which the needs of individual patients are matched to the properties of individual drugs is more appropriate. [ 4 ] [ 3 ]  Although atypical antipsychotics are thought to be safer than typical antipsychotics, they still have severe side effects, including  tardive dyskinesia  (a serious movement disorder),  neuroleptic malignant syndrome , and increased risk of  stroke ,  sudden cardiac death ,  blood clots , and  diabetes .  Significant weight gain  may occur. Critics have argued that "the time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction." [ 6 ]


Atypical antipsychotics are typically used to treat  schizophrenia  or  bipolar disorder . [ 7 ]  They are also frequently used to treat  agitation  associated with  dementia ,  anxiety disorder ,  autism spectrum disorder ,  persecutory delusion  and  obsessive-compulsive disorder  (an  off-label use ). [ 8 ] [ 9 ]  In dementia, they should only be considered after other treatments have failed and if the patient is a risk to themselves and/or others. [ 10 ]


The first-line psychiatric treatment for schizophrenia is antipsychotic medication, [ 11 ]  which can reduce the positive symptoms of schizophrenia in about 8–15 days. Antipsychotics only appear to improve secondary  negative symptoms  of schizophrenia in the short term and may worsen negative symptoms overall. [ 12 ]  Overall there is no good evidence that atypical antipsychotics have any therapeutic benefit for treating the negative symptoms of schizophrenia. [ 13 ]


There is very little evidence on which to base a risk and benefit assessment of using antipsychotics for long-term treatment. [ 14 ]


The choice of which antipsychotic to use for a specific patient is based on benefits, risks, and costs. [ 15 ]  It is debatable whether, as a class,  typical  or atypical antipsychotics are better. [ 16 ]  Both have equal drop-out and symptom relapse rates when typicals are used at low to moderate dosages. [ 17 ]  There is a good response in 40–50% of patients, a partial response in 30–40%, and treatment resistance (failure of symptoms to respond satisfactorily after six weeks to two of three different antipsychotics) in the remaining 20%. [ 18 ]   Clozapine  is considered a first choice treatment for  treatment resistant schizophrenia , especially in the short term; in the longer-terms the risks of adverse effects complicate the choice. [ 19 ]  In turn, risperidone, olanzapine, and  aripiprazole  have been recommended for the treatment of first-episode psychosis. [ 20 ] [ 21 ]


The utility of broadly grouping the antipsychotics into first generation and atypical categories has been challenged. It has been argued that a more nuanced view, matching the properties of individual drugs to the needs of specific patients is preferable. [ 3 ]  While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and  extrapyramidal symptoms  in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring. [ 22 ] [ 23 ]  In 2005 the US government body  NIMH  published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project). [ 24 ]  This study compared several atypical antipsychotics to an older, mid-potency typical antipsychotic,  perphenazine , among 1,493 persons with schizophrenia. The study found that only  olanzapine  outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe  metabolic  effects such as a major weight gain problem (averaging 9.4 lbs over 18 months) and increases in  glucose ,  cholesterol , and  triglycerides . No other atypical studied ( risperidone ,  quetiapine , and  ziprasidone ) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis [ 3 ]  by Leucht  et al.  published in  The Lancet ), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings. [ 25 ]  Compliance has not been shown to be different between the two types. [ 26 ]  Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes. [ 27 ] [ 28 ] [ 29 ]


It has been suggested that there is no validity to the term "second-generation antipsychotic drugs" and that the drugs that currently occupy this category are not identical to each other in mechanism, efficacy, and side-effect profiles. [ 30 ]


Each drug has its own mechanism, as Dr. Rif S. El-Mallakh, explained regarding the binding site and occupancy with a focus on the dopamine D2 receptor:


In general, when an antagonist of a neurotransmitter receptor is used, it must occupy a minimum of 65% to 70% of the target receptor to be effective. This is clearly the case when the target is a postsynaptic receptor, such as the dopamine D2 receptor. Similarly, despite significant variability in antidepressant response, blockade of 65% to 80% of presynaptic transport proteins—such as the serotonin reuptake pumps when considering serotoninergic antidepressants, or the norepinephrine reuptake pumps when considering noradrenergic agents such as nortriptyline—is necessary for these medications to be effective.... Depending on the level of intrinsic activity of a partial agonist and clinical goal, the clinician may aim for a different level of receptor occupancy. For example,  aripiprazole  will act as a dopamine agonist at lower concentrations, but blocks the receptor at higher concentrations. Unlike antagonist antipsychotics, which require only 65% to 70% D2  receptor occupancy  to be effective, aripiprazole receptor binding at effective antipsychotic doses is 90% to 95%. Since aripiprazole has an intrinsic activity of approximately 30% (i.e., when it binds, it stimulates the D2 receptor to about 30% of the effect of dopamine binding to the receptor), binding to 90% of the receptors, and displacing endogenous dopamine, allows aripiprazole to replace the background or tonic tone of dopamine, which has been measured at 19% in people with schizophrenia and 9% in controls. Clinically, this still appears as the minimal effective dose achieving maximal response without significant parkinsonism despite >90% receptor occupancy. [ 31 ]


In bipolar disorder, SGAs are most commonly used to rapidly control  acute mania  and  mixed episodes , often in conjunction with mood stabilizers (which tend to have a delayed onset of action in such cases) such as  lithium  and  valproate . In milder cases of mania or mixed episodes, mood stabilizer monotherapy may be attempted first. [ 32 ]  SGAs are also used to treat other aspects of the disorder (such as acute bipolar depression or as a prophylactic treatment) as adjuncts or as a monotherapy, depending on the drug. Both  quetiapine  and  olanzapine  have demonstrated significant efficacy in all three treatment phases of bipolar disorder.  Lurasidone  (trade name Latuda) has demonstrated some efficacy in the acute depressive phase of bipolar disorder. [ 32 ] [ 33 ] [ 34 ]


In  non-psychotic   major depressive disorder  (MDD), some SGAs have demonstrated significant efficacy as adjunctive agents; and, such agents include: [ 35 ] [ 36 ] [ 37 ] [ 38 ]


whereas only quetiapine has demonstrated efficacy as a monotherapy in non-psychotic MDD. [ 40 ]   Olanzapine/fluoxetine  is an efficacious treatment in both  psychotic  and  non-psychotic  MDD. [ 41 ] [ 42 ]


Aripiprazole ,  brexpiprazole ,  cariprazine ,  olanzapine , and  quetiapine  have been approved as adjunct treatment for MDD by the FDA in the United States. [ 43 ] [ 44 ]   Cariprazine ,  Quetiapine ,  lurasidone , and  lumateperone [ 45 ]  have been approved, as monotherapies, for  bipolar depression , but as of present, lurasidone has not been approved for MDD. [ 43 ]


Both  risperidone  and  aripiprazole  have received FDA approval for irritability in autism. [ 41 ]


Between May 2007 and April 2008, Dementia and Alzheimer's together accounted for 28% of atypical antipsychotic use in patients aged 65 or older. [ 46 ]  The U.S.  Food and Drug Administration  requires that all atypical antipsychotics carry a  black box warning  that the medication has been associated with an increased risk of mortality in elderly patients. [ 46 ]  In 2005, the FDA issued an advisory warning of an increased risk of death when atypical antipsychotics are used in dementia. [ 47 ]  In the subsequent 5 years, the use of atypical antipsychotics to treat dementia decreased by nearly 50%. [ 47 ]  As of now, the only FDA-approved atypical antipsychotic for alzheimer-related dementia is  brexpiprazole .


Legend:


The side effects reportedly associated with the various atypical antipsychotics vary and are medication-specific. Generally speaking, atypical antipsychotics are widely believed to have a lower likelihood for the development of  tardive dyskinesia  than the typical antipsychotics. However, tardive dyskinesia typically develops after long-term (possibly decades) use of antipsychotics. It is not clear if atypical antipsychotics, having been in use for a relatively short time, produce a lower incidence of tardive dyskinesia. [ 32 ] [ 53 ]


Among the other side effects that have been suggested is that atypical antipsychotics increase the risk of cardiovascular disease. [ 54 ]  Kabinoff and colleagues (2003) found that the increase in cardiovascular disease is seen regardless of the treatment received, and that it is instead caused by many different factors such as lifestyle or diet. [ 54 ]


Sexual side effects have also been reported when taking atypical antipsychotics. [ 55 ]  In males antipsychotics reduce sexual interest, impair sexual performance with the main difficulties being failure to ejaculate. [ 56 ]  In females there may be abnormal menstrual cycles and infertility. [ 56 ]  In both males and females the breasts may become enlarged and a fluid will sometimes ooze from the nipples. [ 56 ]  Sexual adverse effects caused by some antipsychotics are a result of an increase of  prolactin . Sulpiride and Amisulpiride, as well as Risperdone and paliperidone (to a lesser extent), cause a high increase of prolactin.


In April 2005, the US Food and Drug Administration (FDA) issued an advisory and subsequent black box warning regarding the risks of atypical antipsychotic use among elderly patients with dementia. The FDA advisory was associated with decreases in the use of atypical antipsychotics, especially among elderly patients with dementia. [ 57 ]  Subsequent research reports confirmed the mortality risks associated with the use of both conventional and atypical antipsychotics to treat patients with dementia. Consequently, in 2008 the FDA issued although a black box warning for classical neuroleptics. Data on treatment efficacies are strongest for atypical antipsychotics. Adverse effects in patients with  dementia  include an increased risk of mortality and cerebrovascular events, as well as metabolic effects, extrapyramidal symptoms, falls, cognitive worsening, cardiac arrhythmia, and pneumonia. [ 58 ]  Conventional antipsychotics may pose an even greater safety risk. No clear efficacy evidence exists to support the use of alternative psychotropic classes (e.g. antidepressants, anticonvulsants). [ 59 ]


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. [ 60 ] [ 61 ] [ 62 ] [ 63 ]


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. [ 64 ]  The typical antipsychotics remain attached to the D2 receptors and accumulate in the brain tissue which may lead to TD. [ 64 ]


Both typical and atypical antipsychotics can cause tardive dyskinesia. [ 65 ]  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. [ 65 ]


Recently, metabolic side effects have been of considerable 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 . [ 66 ]  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. [ 66 ]  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. [ 66 ]  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  H 1  and  5-HT 2C  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  M 3  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  M 3  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 M 3  receptor at therapeutic-relevant concentrations. [ 67 ]


Recent evidence suggests a role of the  α 1  adrenoceptor  and  5-HT 2A  receptor  in the metabolic effects of atypical antipsychotics. The  5-HT 2A  receptor , however, is also believed to play a crucial role in the therapeutic advantages of atypical antipsychotics over their predecessors, the typical antipsychotics. [ 68 ]


The two atypical antipsychotics with trials showing that had a low incidence of weight gain in large meta-analysis were lurasidone and aripiprazole. [ 69 ]  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. [ 70 ]   Aripiprazole ,  asenapine ,  ziprasidone  and  lurasidone  have low propensity to cause weight gain. [ 71 ]  Lumateperone was found to cause minimal weight gain in a long-term 12 month follow-up study. [ 72 ]


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. [ 54 ]  The authors of this study suggest that it is a causal relationship the Kabinoff et al. suggest the findings only suggest a temporal association. [ 54 ]  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. [ 54 ]  Prescribing  topiramate ,  zonisamide ,  metformin ,  GLP-1 receptor agonists , or  nizatidine  alongside an antipsychotic significantly reduces weight gain. [ 73 ]


Despite increasing some  risk factors , SGAs are not associated with excess cardiovascular mortality when used to treat serious psychiatric disorders. [ 74 ]


The  British National Formulary  recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. [ 80 ]  Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. [ 81 ]  Other symptoms may include restlessness, increased sweating, and trouble sleeping. [ 81 ]  Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. [ 81 ]  Symptoms generally resolve after a short period of time. [ 81 ]


There is tentative evidence that discontinuation of antipsychotics can result in psychosis. [ 82 ]  It may also result in reoccurrence of the condition that is being treated. [ 83 ]  Rarely tardive dyskinesia can occur when the medication is stopped. [ 81 ]


The atypical antipsychotics integrate with the  serotonin  (5-HT),  norepinephrine  (α, β), and  dopamine  (DA) receptors in order to effectively treat schizophrenia. [ 84 ]


D 2  Receptor : Hyperactive dopaminergic activity on  D 2  receptors  in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (hallucinations, delusions, paranoia). After taking an antipsychotic,  antagonism  of D 2  receptors occurs throughout the entire brain, leading to a number of deleterious side effects from D 2  receptor antagonism throughout the entire  dopamine pathway  system. It's not possible to affect D 2  receptors only in the  mesolimbic pathway , [ 85 ] [ Stahl AP Explained 1 - 1 ]  but  5-HT 2A  receptor  antagonism reverses these side effects to some extent. [ Stahl AP Explained 1 - 2 ]  Reducing D 2  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 D 2  receptor dopamine activity is sometimes low in schizophrenia, resulting in cognitive, affective, and, broadly, the negative symptoms of schizophrenia. D 2  receptor antagonism further compounds these problems. In the  nigrostriatal pathway , D 2  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 , D 2  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 . [ Stahl AP Explained 1 - 1 ]


5-HT 2A  Receptor : When  serotonin  is released on to  postsynaptic  5-HT 2A  receptors, the dopamine neuron is inhibited, thus acting as a brake on dopamine release. [ Stahl AP Explained 1 - 2 ]  This brake is disrupted through action of a 5-HT 2A  antagonist, which disinhibits the dopamine neuron, stimulating dopamine release. The result of this is that dopamine competes with antipsychotic D 2  antagonistic action at D 2  receptors, thereby reducing antagonistic binding there and eliminating or lowering D 2  antagonistic effects in several pathways of the dopamine system. [ Stahl AP Explained 1 - 2 ]  In the nigrostratial pathway, it reduces EPS. In the tuberoinfundibular pathway, it reduces or eliminates prolactin elevation. [ Stahl AP Explained 1 - 3 ]  Dopamine release in the mesolimbic pathway from 5-HT 2A  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 D 2  antagonism. [ Stahl AP Explained 1 - 3 ]  When 5-HT 2A  antagonistic agent particles occupy 5-HT 2A  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. [ Stahl AP Explained 1 - 3 ]  Furthermore, 5-HT 2A  receptor antagonism blocks the serotonergic excitation of cortical pyramidal cells, reducing  glutamate  release, which in turn lowers hyperactive dopaminergic D 2  receptor activity in the mesolimbic pathway, reducing or eliminating the positive symptoms of schizophrenia. [ Stahl AP Explained 1 - 3 ] [ 86 ] [ 87 ]


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-HT 2A .


Some effects of  5-HT 1A  receptor activation include decreased aggressive behavior/ideation, [ 88 ]  increased sociability, and decreased anxiety and depression. [ non-primary source needed ]  Blockade of the 5-HT 2C  receptor increases  serotonin , releasing norepinephrine and dopamine within the brain. [ 85 ]  But neuronal  reuptake  of norepinephrine is  limited sharply  by some antipsychotics, e.g.  ziprasidone . Increased norepinephrine can cause increased glucose(blood sugar) levels. [ 89 ] [ 90 ] [ 91 ]  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. [ 92 ] [ 93 ] [ 94 ] [ 95 ] [ 96 ]  Inhibition of norepinephrine stabilizes mood in humans. [ 97 ]   5-HT 6  receptor antagonists improve cognition, learning, and memory. [ 98 ]  The  5-HT 7  receptor is very potent for the mitigation of bipolar conditions and also yields an antidepressant effect. The antipsychotics  asenapine , [ 99 ]   lurasidone , [ 100 ] [ 101 ]   risperidone , [ 102 ]  and  aripiprazole [ 103 ]  are very potent at the 5-HT 7  receptor.  Antagonistic affinity  for the  H 1  receptor also has an antidepressant effect. H 1  antagonism blocks serotonin and norepinephrine reuptake. Patients with increased histamine levels have been observed to have lower serotonin levels. [ 104 ]  However, the H 1  receptor is linked to weight gain. To have partial agonism at the  5-HT 1A  receptor can yield absence of weight gain in an antipsychotic. This is very relevant for ziprasidone, [ 105 ] [ 106 ]  but it creates a risk for a prolonged QTc interval. [ 107 ] [ 108 ]  On the other hand, blockade of the  5-HT 3  receptor removes the risk for a prolonged QTc interval, [ 100 ]  but then creates a larger risk for weight gain. Relation to the 5-HT 3  receptor increases caloric uptake and glucose, [ 109 ]  which is seen in clozapine and olanzapine. [ 110 ] [ 111 ]  Other ways for dopamine to resolve is to have agonism at both the D 2  receptor and 5-HT 1A  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 D 2  receptors in the mesolimbic pathway, which is mediated in some part by antipsychotics (and despite dopamine release in the mesocortical pathway from 5-HT 2A  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. [ 85 ]


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 . [ citation needed ]


Note:  Unless otherwise specified, the drugs below serve as antagonists/inverse agonists at the receptors listed.


Atypical antipsychotics are most commonly administered orally. [ 56 ]  Antipsychotics can also be injected, but this method is not as common. [ 56 ]  They are lipid-soluble, are readily absorbed from the digestive tract, and can easily pass the blood–brain barrier and placental barriers. [ 56 ]  Once in the brain, the antipsychotics work at the synapse by binding to the receptor. [ 113 ]  Antipsychotics are completely metabolized in the body and the metabolites are excreted in urine. [ 56 ]  These drugs have relatively long half-lives. [ 56 ]  Each drug has a different half-life, but the occupancy of the D2 receptor falls off within 24 hours with atypical antipsychotics, while lasting over 24 hours for the typical antipsychotics. [ 64 ]  This may explain why relapse into psychosis happens quicker with atypical antipsychotics than with typical antipsychotics, as the drug is excreted faster and is no longer working in the brain. [ 64 ]  Physical dependence with these drugs is very rare. [ 56 ]  However, if the drug is abruptly discontinued, psychotic symptoms, movement disorders, and sleep difficulty may be observed. [ 56 ]  It is possible that withdrawal is rarely seen because the AAP are stored in body fat tissues and slowly released. [ 56 ]


Acronyms used:
IR - Immediate release formulation.
XR - Extended release formulation.
EM - Extensive metabolisers.
PM - Poor metabolisers.
C max  - maximum plasma concentrations of the drug.


The first major tranquilizer or antipsychotic medication,  chlorpromazine  (Thorazine), a typical antipsychotic, was discovered in 1951 and introduced into clinical practice shortly thereafter. Clozapine (Clozaril), an atypical antipsychotic, fell out of favor due to concerns over drug-induced  agranulocytosis . Following research indicating its effectiveness in treatment-resistant  schizophrenia  and the development of an adverse event monitoring system, clozapine re-emerged as a viable antipsychotic. According to Barker (2003), the three most-accepted atypical drugs are clozapine, risperidone, and olanzapine. However, he goes on to explain that clozapine is usually the last resort when other drugs fail. Clozapine can cause agranulocytosis (a decreased number of white blood cells), requiring blood monitoring for the patient. Despite the effectiveness of clozapine for treatment-resistant schizophrenia, agents with a more favorable side-effect profile were sought for widespread use. During the 1990s,  olanzapine ,  risperidone , and  quetiapine  were introduced, with  ziprasidone  and  aripiprazole  following in the early 2000s. The atypical antipsychotic  paliperidone  was approved by the FDA in late 2006. [ citation needed ]


The atypical antipsychotics have found favor among clinicians and are now considered to be  first-line treatments  for schizophrenia and are gradually replacing the  typical antipsychotics . In the past, most researchers have agreed that the defining characteristics of atypical antipsychotics are the decreased incidence of  extrapyramidal  side effects (EPS) [ 132 ]  and an absence of sustained prolactin elevation. [ 64 ]


The terminology can still be imprecise. The definition of "atypicality" was based upon the absence of extrapyramidal side effects, but there is now a clear understanding that atypical antipsychotics can still induce these effects (though to a lesser degree than typical antipsychotics). [ 133 ]  Recent literature focuses more upon specific pharmacological actions and less upon categorization of an agent as "typical" or "atypical". There is no clear dividing line between the typical and atypical antipsychotics therefore categorization based on the action is difficult. [ 64 ]


More recent research is questioning the notion that second-generation antipsychotics are superior to first generation typical antipsychotics. Using a number of parameters to assess quality of life,  Manchester University  researchers found that typical antipsychotics were no worse than atypical antipsychotics. The research was funded by the  National Health Service  (NHS) of the UK. [ 134 ]  Because each medication (whether first or second generation) has its own profile of desirable and adverse effects, a neuropsychopharmacologist may recommend one of the older ("typical" or first generation) or newer ("atypical" or second generation) antipsychotics alone or in combination with other medications, based on the symptom profile, response pattern, and adverse effects history of the individual patient.


Between May 2007 and April 2008, 5.5 million Americans filled at least one prescription for an atypical antipsychotic. [ 46 ]  In patients under the age of 65, 71% of patients were prescribed an atypical antipsychotic to treat Schizophrenia or Bipolar Disorder where this dropped to 38% in patients aged 65 or above. [ 46 ]


Despite the name "antipsychotics", the drugs are commonly used for a variety of conditions that do not involve  psychosis . Some healthcare professionals reported avoiding the name "atypical antipsychotic" when prescribing the drug to patients who had bipolar disorder. [ 135 ]


Stahl: AP Explained 1


NM_016574 NM_000795


NP_000786 NP_057658 NP_000786.1


Dopamine receptor D 2 , also known as  D 2 R , is a  protein  that, in humans, is encoded by the  DRD2   gene . After work from  Paul Greengard 's lab had suggested that  dopamine receptors  were the site of action of antipsychotic drugs, several groups, including those of  Solomon H. Snyder  and  Philip Seeman  used a radiolabeled antipsychotic drug to identify what is now known as the  dopamine  D 2  receptor. [ 5 ]  The dopamine D 2  receptor is the main  receptor  for most  antipsychotic drugs .  The structure of DRD2 in complex with the atypical antipsychotic  risperidone  has been determined. [ 6 ] [ 7 ]


D 2  receptors are coupled to  G i  subtype of  G protein . This  G protein-coupled receptor  inhibits  adenylyl cyclase  activity. [ 8 ]


In mice, regulation of D 2 R surface expression by the  neuronal calcium sensor-1  (NCS-1) in the  dentate gyrus  is involved in exploration,  synaptic plasticity  and memory formation. [ 9 ]  Studies have shown potential roles for D 2 R in retrieval of fear memories in the  prelimbic cortex [ 10 ]  and in discrimination learning in the  nucleus accumbens . [ 11 ]


In flies, activation of the D 2   autoreceptor  protected dopamine neurons from cell death induced by  MPP + , a toxin mimicking  Parkinson's disease  pathology. [ 12 ]


While optimal dopamine levels favor D 1 R cognitive stabilization, it is the D 2 R that mediates the cognitive flexibility in humans. [ 13 ] [ 14 ] [ 15 ]


Alternative splicing  of this gene results in three transcript variants encoding different  isoforms . [ 16 ]


The long form ( D2Lh ) has the "canonical" sequence and functions as a classic post- synaptic  receptor. [ 17 ]  The short form ( D2Sh ) is pre-synaptic and functions as an  autoreceptor  that regulates the levels of dopamine in the synaptic cleft. [ 17 ]   Agonism  of D2sh receptors inhibits dopamine release; antagonism increases  dopaminergic  release. [ 17 ]  A third D2(Longer) form differs from the canonical sequence where 270V is replaced by VVQ. [ 18 ]


D 2 R conformers are equilibrated between two full active (D 2 High R) and inactive (D 2 Low R) states, while in complex with an  agonist  and  antagonist  ligand, respectively.


The monomeric inactive conformer of D 2 R in binding with  risperidone  was reported in 2018 ( PDB  ID: 6CM4). However, the active form which is generally bound to an agonist, is not available yet and in most of the studies the  homology modeling  of the structure is implemented. The difference between the active and inactive of  G protein-coupled receptor  is mainly observed as conformational changes at the cytoplasmic half of the structure, particularly at the  transmembrane domains  (TM) 5 and 6. The conformational transitions occurred at the cytoplasmic ends are due to the coupling of  G protein  to the cytoplasmic loop between the TM 5 and 6. [ 19 ]


It was observed that either D 2 R agonist or antagonist ligands revealed better  binding affinities  inside the ligand-binding domain of the active D 2 R in comparison with the inactive state. It demonstrated that ligand-binding domain of D 2 R is affected by the conformational changes occurring at the cytoplasmic domains of the TM 5 and 6. In consequence, the D 2 R activation reflects a positive cooperation on the ligand-binding domain.


In drug discovery studies in order to calculate the binding affinities of the D 2 R ligands inside the binding domain, it's important to work on which form of D 2 R. It's known that the full active and inactive states are recommended to be used for the agonist and antagonist studies, respectively.


Any disordering in equilibration of D 2 R states, which causes problems in signal transferring between the nervous systems, may lead to diverse serious disorders, such as  schizophrenia , [ 20 ]   autism [ citation needed ]  and  Parkinson's disease . [ citation needed ]  In order to assist in the management of these conditions, equilibration between the D 2 R states is controlled by implementing of agonist and antagonist D 2 R ligands. [ citation needed ]  In most cases, it was observed that the problems regarding the D 2 R states may have genetic roots and are controlled by drug therapies. [ citation needed ]  So far, there is no certain treatment for these mental disorders.


There is an orthosteric binding site (OBS), as well as a secondary binding pocket (SBP) on the dopamine 2 receptor, and interaction with the SBP is a requirement for allosteric pharmacology. The compound SB269652 is a negative allosteric modulator of the D 2 R. [ 21 ]


It was observed that D 2 R exists in dimeric forms or higher order oligomers. [ 22 ]  There are some experimental and molecular modeling evidences that demonstrated the D 2 R monomers cross link from their TM 4 and TM 5 to form dimeric conformers. [ 23 ] [ 24 ]


Allelic  variants:


Some researchers have previously associated the  polymorphism  Taq 1A ( rs1800497 ) to the  DRD2  gene.
However, the polymorphism resides in  exon  8 of the  ANKK1  gene. [ 28 ]  DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor
fluctuations but not hallucinations in Parkinson's disease. [ 29 ] [ 30 ]  A splice variant in Dopamine receptor D2(rs1076560) was found to be associated with limb truncal  tardive dyskinesia  and diminished expression factor of  Positive and Negative Syndrome Scale  (PANSS) in  schizophrenia  subjects. [ 31 ]


Most of the older  antipsychotic  drugs such as  chlorpromazine  and  haloperidol  are antagonists for the dopamine D 2  receptor, but are, in general, very unselective, at best selective only for the "D 2 -like family" receptors and so binding to D 2 , D 3  and D 4 , and often also to many other receptors such as those for  serotonin  and  histamine , resulting in a range of side-effects and making them poor agents for scientific research. In similar manner, older dopamine agonists used for  Parkinson's disease  such as  bromocriptine  and  cabergoline  are poorly selective for one dopamine receptor over another, and, although most of these agents do act as D 2  agonists, they affect other subtypes as well. Several selective D 2   ligands  are, however, now available, and this number is likely to increase as further research progresses.


The dopamine receptor D 2  has been shown to  interact  with  EPB41L1 , [ 50 ]   PPP1R9B [ 51 ]  and  NCS-1 . [ 52 ]


The D 2  receptor forms  receptor heterodimers   in vivo  (i.e., in living animals) with other  G protein-coupled receptors ; these include: [ 53 ]


The D 2  receptor has been shown to form heterodimers  in vitro  (and possibly  in vivo ) with  DRD 3 , [ 56 ]   DRD 5 , [ 57 ]  and  5-HT 2A . [ 58 ]


Insulin shock therapy  or  insulin coma therapy  was a form of  psychiatric  treatment in which patients were repeatedly injected with large doses of  insulin  in order to produce daily  comas  over several weeks. [ 1 ]  It was introduced in 1927 by Austrian-American  psychiatrist   Manfred Sakel  and used extensively in the 1940s and 1950s, mainly for  schizophrenia , before falling out of favour and being replaced by  neuroleptic  drugs in the 1960s. [ 2 ]


It was one of a number of physical treatments introduced into psychiatry in the first four decades of the 20th century. These included the convulsive therapies ( cardiazol/metrazol  therapy and  electroconvulsive therapy ),  deep sleep therapy , and  psychosurgery . Insulin coma therapy and the convulsive therapies are collectively known as the  shock therapies .


In 1927, Sakel, who had recently qualified as a medical doctor in  Vienna  and was working in a psychiatric clinic in  Berlin , began to use low (sub-coma) doses of insulin to treat drug addicts and psychopaths, and when one of the patients experienced improved mental clarity after having slipped into an accidental coma, Sakel reasoned the treatment might work for mentally ill patients. [ 3 ]  Having returned to Vienna, he treated schizophrenic patients with larger doses of insulin in order to deliberately produce coma and sometimes convulsions. [ 3 ]  Sakel made his results public in 1933, and his methods were soon taken up by other psychiatrists. [ 3 ]


Joseph Wortis , after seeing Sakel practice it in 1935, introduced it to the US. British psychiatrists from the  Board of Control  visited Vienna in 1935 and 1936, and by 1938, 31 hospitals in England and Wales had insulin treatment units. [ 2 ]  In 1936, Sakel moved to New York and promoted the use of insulin coma treatment in US psychiatric hospitals. [ 3 ]  By the late 1940s, the majority of psychiatric hospitals in the US were using insulin coma treatment. [ 4 ]


Insulin coma therapy was a labour-intensive treatment that required trained staff and a special unit. [ 2 ]  Patients, who were almost invariably diagnosed with  schizophrenia , were selected on the basis of having a good  prognosis  and the physical strength to withstand an arduous treatment. [ 5 ]  There were no standard guidelines for treatment. Different hospitals and psychiatrists developed their own protocols. [ 5 ]  Typically, injections were administered six days a week for about two months. [ 1 ]


The daily insulin dose was gradually increased to 100–150 units (1 unit = 34.7  μg [ 6 ] ) until comas were produced, at which point the dose would be levelled out. [ 1 ]  Occasionally doses of up to 450 units were used. [ 7 ]  After about 50 or 60 comas, or earlier if the psychiatrist thought that maximum benefit had been achieved, the dose of insulin was rapidly reduced before treatment was stopped. [ 5 ] [ 8 ]  Courses of up to 2 years have been documented. [ 8 ]


After the insulin injection patients would experience various symptoms of decreased blood glucose: flushing, pallor, perspiration, salivation, drowsiness or restlessness. [ 8 ]   Sopor  and coma—if the dose was high enough—would follow. [ 8 ]  Each coma would last for up to an hour and be terminated by intravenous glucose or via naso-gastric tube. [ 1 ]  Seizures occurred before or during the coma. [ 9 ]  Many would be tossing, rolling, moaning, twitching, spasming or thrashing around. [ 5 ]


Some psychiatrists regarded seizures as therapeutic and patients were sometimes also given  electroconvulsive therapy  or cardiazol/metrazol convulsive therapy during the coma, or on the day of the week when they didn't have insulin treatment. [ 8 ] [ 9 ]  When they were not in a coma, insulin coma patients were kept together in a group and given special treatment and attention. One handbook for psychiatric nurses, written by British psychiatrist  Eric Cunningham Dax , instructs nurses to take their insulin patients out walking and occupy them with games and competitions, flower-picking and map-reading, etc. [ 10 ]  Patients required continuous supervision as there was a danger of hypoglycemic aftershocks after the coma. [ 2 ]


In "modified insulin therapy", used in the treatment of neurosis, patients were given lower (sub-coma) doses of insulin. [ 8 ]


A few psychiatrists (including Sakel) claimed success rates for insulin coma therapy of over 80% in the treatment of schizophrenia. [ 11 ]  A few others argued that it merely accelerated remission in those patients who were undergoing remission anyway. The consensus at the time was somewhere in between, claiming a success rate of about 50% in patients who had been ill for less than a year (about double the spontaneous remission rate) with no influence on relapse. [ 3 ] [ 12 ]


Sakel suggested the therapy worked by "causing an intensification of the tonus of the parasympathetic end of the autonomic nervous system, by blockading the nerve cell, and by strengthening the anabolic force which induces the restoration of the normal function of the nerve cell and the recovery of the patient." [ 3 ]  The shock therapies in general had developed on the erroneous premise that  epilepsy  and schizophrenia rarely occurred in the same patient. The premise was supported by neuropathologic studies that found a dearth of glia in the brains of schizophrenic patients and a surplus of glia in epileptic brains. These observations led the Hungarian neuropsychiatrist  Ladislas Meduna  to induce seizures in schizophrenic patients with injections of camphor, soon replaced by pentylenetetrazol (Metrazole). [ 13 ]  Another theory was that patients were somehow "jolted" out of their mental illness. [ 14 ]


The  hypoglycemia  (pathologically low  glucose  levels) that resulted from insulin coma therapy made patients extremely restless, sweaty, and liable to further convulsions and "after-shocks". In addition, patients invariably emerged from the long course of treatment "grossly  obese ", [ 5 ]  probably due to glucose rescue-induced  glycogen storage disease . The most severe risks of insulin coma therapy were death and brain damage, resulting from irreversible or prolonged coma respectively. [ 1 ] [ 7 ]  A study at the time claimed that many of the cases of brain damage were actually therapeutic improvement because they showed "loss of tension and hostility". [ 15 ]  Mortality risk estimates varied from about 1% [ 2 ]  to 4.9%. [ 16 ]


Respected singer-songwriter  Townes Van Zandt  was said to have lost much of his long-term memory from this treatment, performed on him for  bipolar disorder , preceding a life of  substance abuse  and  depression . [ 17 ]


Insulin coma therapy was used in most hospitals in the US and the UK during the 1940s and 1950s. The numbers of patients were restricted by the requirement for intensive medical and nursing supervision and the length of time it took to complete a course of treatment. For example, at one typical large British psychiatric hospital,  Severalls Hospital  in  Essex , insulin coma treatment was given to 39 patients in 1956. In the same year, 18 patients received modified insulin treatment, while 432 patients were given electroconvulsive treatment. [ 18 ]


In 1953, British psychiatrist Harold Bourne published a paper entitled "The insulin myth" in the  Lancet , in which he argued that there was no sound basis for believing that insulin coma therapy counteracted the schizophrenic process in a specific way. If treatment worked, he said, it was because patients were chosen for their good prognosis and were given special treatment: "insulin patients tend to be an elite group sharing common privileges and perils". [ 19 ]  Prior to publishing "The insulin myth" in  The Lancet , Bourne had tried to submit the article to the  Journal of Mental Science ; after a 12-month delay, the Journal informed Bourne they had rejected the article, telling him to "get more experience". [ 20 ]


In 1957, when insulin coma treatment use was declining,  The Lancet  published the results of a randomized, controlled trial in which patients were either given insulin coma treatment or identical treatment but with unconsciousness produced by  barbiturates . There was no difference in outcome between the groups and the authors concluded that, whatever the benefits of the coma regimen, insulin was not the specific therapeutic agent. [ 21 ]


In 1958, American neuropsychiatrist Max Fink published in the Journal of the American Medical Association the results of a random controlled comparison in 60 patients treated with 50 iatrogenic insulin-induced comas or chlorpromazine in doses from 300 mg to 2000 mg/day. [ 22 ]  The results were essentially the same in relief and discharge ratings but chlorpromazine was safer with fewer side-effects, easier to administer, and better suited to long-term care. [ citation needed ]


In 1958, Bourne published a paper on increasing disillusionment in the psychiatric literature about insulin coma therapy for schizophrenia. He suggested there were several reasons it had received almost universal uncritical acceptance by reviews and textbooks for several decades despite the occasional disquieting negative finding, including that, by the 1930s when it all started, schizophrenics were considered inherently unable to engage in  psychotherapy , and insulin coma therapy "provided a personal approach to the schizophrenic, suitably disguised as a physical treatment so as to slip past the prejudices of the age." [ 23 ]


By the 1970s, insulin shock therapy had mostly fallen out of use in the United States, though was still practiced in some hospitals. [ 24 ]  Its use may have continued longer in China, India, and the Soviet Union. [ 20 ] [ 25 ]


Recent articles about insulin coma treatment have attempted to explain why it was given such uncritical acceptance. In the US, Deborah Doroshow wrote that insulin coma therapy secured its foothold in psychiatry not because of scientific evidence or knowledge of any mechanism of therapeutic action, but due to the impressions it made on the minds of the medical practitioners within the local world in which it was administered and the dramatic recoveries observed in some patients. Today, she writes, those who were involved are often ashamed, recalling it as unscientific and inhumane. Administering insulin coma therapy made psychiatry seem a more legitimate medical field. Harold Bourne, who questioned the treatment at the time, said: "It meant that psychiatrists had something to do. It made them feel like real doctors instead of just institutional attendants". [ 5 ]


One retired psychiatrist who was interviewed by Doroshow "described being won over because his patients were so sick and alternative treatments did not exist". [ 5 ]  Doroshow argues that "psychiatrists used complications to exert their practical and intellectual expertise in a hospital setting" and that collective risk-taking established "especially tight bonds among unit staff members". [ 5 ]  She finds it ironic that psychiatrists "who were willing to take large therapeutic risks were extremely careful in their handling of adverse effects". Psychiatrists interviewed by Doroshow recalled how insulin coma patients were provided with various routines and recreational and group-therapeutic activities, to a much greater extent than most psychiatric patients. Insulin coma specialists often chose patients whose problems were the most recent and who had the best  prognosis ; in one case discussed by Doroshow a patient had already started to show improvement before insulin coma treatment, and after the treatment denied that it had helped, but the psychiatrists nevertheless argued that it had. [ 5 ]


In 1959, the 1994  Nobel Prize  winner in Economics,  John Nash , was diagnosed with schizophrenia and was initially treated at McLean Hospital. When he relapsed, he was admitted to  Trenton Psychiatric Hospital  in  New Jersey . His associates at  Princeton University  pleaded with the hospital director to have Nash admitted to the insulin coma unit, recognizing that it was better staffed than other hospital units. He responded to treatment and was subsequently medicated with  neuroleptics . [ 26 ]


Nash's life story was presented in the film  A Beautiful Mind , which accurately portrayed the seizures associated with his treatments. [ 27 ]   In a review of the Nash history, Fink ascribed the success of coma treatments to the 10% of associated seizures, noting that physicians often augmented the comas by convulsions induced by  ECT . He envisioned insulin coma treatment as a weak form of convulsive therapy. [ 28 ]


In the UK, psychiatrist Kingsley Jones sees the support of the Board of Control as important in persuading psychiatrists to use insulin coma therapy. The treatment then acquired the privileged status of a standard procedure, protected by professional organizational interests. He also notes that it has been suggested that the  Mental Treatment Act 1930  encouraged psychiatrists to experiment with physical treatments. [ 2 ]


British lawyer Phil Fennell notes that patients "must have been terrified" by the insulin coma therapy procedures and the effects of the massive overdoses of insulin, and were often rendered more compliant and easier to manage after a course. [ 14 ]


Leonard Roy Frank , an American activist from the  psychiatric survivors movement  who underwent 50 forced insulin coma treatments combined with ECT, described the treatment as "the most devastating, painful and humiliating experience of my life", a "flat-out atrocity" glossed over by psychiatric  euphemism , and a violation of basic human rights. [ 29 ]


In 2013, French physician-and-novelist  Laurent Seksik  wrote an historical novel about the tragic life of  Eduard Einstein :  Le cas Eduard Einstein . He related the encounter between Dr Sakel and  Mileva Maric ,  Albert Einstein 's first wife (and Eduard's mother), and the way Sakel's therapy had been given to Eduard, who had  schizophrenia . [ 30 ]


Like many new medical treatments for diseases previously considered incurable, depictions of insulin coma therapy in the media were initially favorable. In the 1940 film  Dr. Kildare's Strange Case , young Kildare uses the new "insulin shock cure for schizophrenia" to bring a man back from insanity. The film dramatically shows a five-hour treatment that ends with a patient eating jelly sandwiches and reconnecting with his wife. Other films of the era began to show a more sinister approach, beginning with the 1946 film  Shock , in which actor  Vincent Price  plays a doctor who plots to murder a patient using an overdose of insulin in order to keep the fact that he was a murderer a secret. More recent films include  Frances  (1982) in which actress  Frances Farmer  undergoes insulin coma treatment, and  A Beautiful Mind , which depicted genius  John Nash  undergoing insulin treatment. In an episode of the medical drama  House M.D. , House puts himself in an insulin shock to try to make his hallucinations disappear. [ 31 ]   Sylvia Plath 's  The Bell Jar  refers to insulin coma therapy in chapter 15. In  Kelly Rimmer 's book,  The German Wife , the character Henry Davis undergoes insulin shock therapy to treat 'combat fatigue'.


The  Journal of Child and Adolescent Psychopharmacology  is a  peer-reviewed   medical journal  covering  psychopharmacology  in  children  and  adolescents . It was established in 1990 and is published ten times per year by  Mary Ann Liebert . The  editor-in-chief  is  Harold S. Koplewicz  (Child Mind Institute). According to the  Journal Citation Reports , the journal has a 2017  impact factor  of 2.901. [ 1 ]


Electroencephalography  (EEG) is the science of recording the spontaneous rhythmic electrical activity of a living brain through electrodes on the scalp. Brain rhythms have origins similar to the electrical activity of the heart.  The rhythmic activity varies in frequency and amplitude with age, attention, sleep, and chemical concentrations of oxygen, carbon dioxide, glucose, ammonia, and hormones. Chemicals that affect brain functions change brain rhythms in systematic and identifiable ways. As new psychoactive drugs were discovered that changed behavior, the basis for the science of  psychopharmacology , the accompanying changes in the rhythms were found to be drug class specific.  The measurement of the changes in rhythms became the basis for the science of pharmaco-EEG.


Definitions of the changes in EEG rhythms were developed that identified and classified psychoactive drugs, monitored the depth of anesthesia, and evaluated the efficacy of the seizures induced in convulsive therapy (electroshock).


The first recordings of electrical activity from the brain were reported from exposed animal brain tissues in the 1870s. In 1929 Hans Berger, a German psychiatrist, reported continuous electrical rhythms from the intact human head using electrodes on the scalp.  The continuous electrical activity varied in frequencies and amplitude with drowsiness and sleep, and with mental problem solving.  Episodic runs and bursts of high voltage slow frequencies were recorded in patients with epilepsy.


In his third report in 1931 Berger recorded changes in the rhythms with cocaine, morphine, scopolamine, and chloroform. Each chemical elicited different frequency and amplitude patterns and different behaviors.


The first clinical applications were in identifying the sudden bursts of high voltage slow frequencies during seizures, both spontaneous and induced by the chemical pentylenetetrazol (Metrazol), by electricity in electroshock, and in the coma induced by insulin.  When reserpine was studied in 1953, chlorpromazine in 1954, and imipramine in 1957, individual rhythmic patterns were described.


The EEG patterns of new psychoactive drugs predicted their clinical activity.  By the 1960s, EEG analysis of psychoactive drugs was a feature of the NIMH Early Clinical Drug Evaluation (ECDEU) program that evaluated and identified new psychiatric treatments. Proposed psychoactive drugs developed in chemical laboratories were first tested in animals and then tested in man.  The changes in the EEG became the basis for a classification of new drugs.


Assessment methods in human volunteers were developed that recorded the changes in the resting subject at different dosages, both on acute single administrations and repeated daily dosing. The observed changes were compared to those for known drugs and predicted their behavioral effects. When no systematic changes were recorded, the agents were considered not to have a clinical use.


Dosing schedules were optimized.  In patients who failed to respond to prescribed treatments, those who were considered "pharmacotherapy resistant," EEG studies showed that the chemicals did not elicit identifiable brain changes.


In pre-clinical animal trials EEG recordings were associated the changes with vigilance and motor measures, concluding that the EEG patterns were "dissociated," that is, bearing little relationship to the changes in behavior.  In human trials, however, when the EEG measures could be related to vigilance, mood, memory, and psychological tests, a theory of "association of EEG and behavior" developed and sustained pharmaco-EEG studies of new drugs.


The technology was applied in anesthesia, identifying the efficacy of individual seizures in convulsive therapy, in studies of sleep patterns, and the relation of evoked potentials to speech and psychological tests.


Social changes in attitudes to the ethics of testing drugs and treatments in patients, prisoners, children, and volunteers inhibited the continued development of the science and its abandonment.


Polypharmacy and the widespread use of active psychiatric drugs made the study of individual compounds in psychiatric patients difficult.  The science then successfully focused on alert male volunteers (since the EEG varied with menstrual cycles in women). [ citation needed ]


Vigilance.  The scalp recorded EEG is sensitive to changes in vigilance.  Different methods developed to sustain a monitored level of alertness using hand held buzzers that sounded off when the subject relaxed and dozed.


Volunteer Baseline and Placebo training.  As the EEG is sensitive to anxiety, an initial training session became standard procedure. The baseline recording identified subjects whose records were unique.


EEG recording.  Different electrode placements were tested. Commonly the recordings were made using the frontal-occipital or the bifrontal leads. Standard EEG amplifiers were used.


Quantification and analyses. In the beginning the EEG recordings were made on paper and changes measured visually, scored by ruler and calipers. By the 1960s, electronic analyzers of 10 second epochs measured changes in "power."   Digital computer methods using period analysis, power spectral density, and amplitude analyses followed.


The quantitative changes in mean frequency, mean amplitudes, percent time delta (1–3 Hz), theta (3.5 - 7.5 Hz), alpha (8-12.5 Hz), beta1 (13–21 Hz), and beta2 (>21 Hz), and the presence of bursts in 10-second epochs were commonly used to identify patterns.


Predictive patterns.  The measures related the EEG changes to the common classes of psychoactive drugs—antidepressant,  anxiolytic ,  antipsychotic , hallucinogen,  deliriant ,  euphoriant , and mood stabilizer being the most frequent.  For a time, the pharmaco-EEG profiles of different classes of drugs were actively used to identify active psychotropic agents.


Psychopharmacology.  Pharmaco-EEG studies were economically useful in clinically classifying new agents, dosage ranges and durations of effects, and separating active from inactive substances.  The list of successful applications is extensive; some specific examples are the identification of mianserin (GB-94) and doxepin as antidepressants of the imipramine class; of the inactivity of flutroline as a proposed antipsychotic in man despite activity in dogs; and of equivalent EEG activity of the laevo and dextro enantiomers of 6-azamianserin (mirtazapine) despite differences in preclinical trials.


Studies of different cannabis formulations (hashish, marijuana, tetrahydrocannabinol-∆-9 extract each showed the same patterns in EEG, cardiovascular, and clinical profiles. Tolerance development was marked in acute administration of cannabis in chronic hashish users.


In testing narcotic antagonists ( naloxone ,  cyclazocine ) and opioid substitutes ( methadone ,  levomethadyl ) in the treatment of opioid dependence, the quantitative EEG experiments showed the efficiency of antagonistic and replacement activity of different dosing schedules. Dose finding trials of naloxone showed no specific CNS effect when administered alone but very effective antagonistic action in opioid dose and overdose.


Convulsive therapy.  The grandmal seizure is the central event in electroshock (electroconvulsive therapy, ECT) and insulin coma.  It was introduced in 1934 and by the 1940s EEG recordings during the treatment showed the classic sequence of epileptic seizure events recognized as the "grand mal seizure."  In the 1950s, recordings of interseizure records, on days after an induced seizure, showed progressive slowing of mean frequencies and increased amplitudes during the treatment course.  These changes were necessary accompaniments of effective courses of treatment—patients without progressive slowing failed to recover.


In the early 1980s, commercial ECT devices were equipped with a 2-channel EEG recorder that measured the EEG characteristics and duration.  The quality of the EEG record became the standard for an "effective" treatment.  The same quantitative measures used in psychopharmacology were established in clinical ECT.


Anesthesia.  Specialized equipment to monitor ongoing identification of anesthesia stages are common in modern surgical units.


History.


Fink M. Pharmacoelectroenephalography: A note on its history. Neuropsychobiology 1984; 12:173-178


Fink M. A clinician-researcher and ECDEU: 1959-1980. In: T. Ban, D. Healy, E. Shorter (Eds.):  The Triumph of Psychopharmacology and the Story of the CINP. Budapest, Animula,  82-96, 2000.


Fink M. Pharmaco-Electroencephalography: A  Selective History of the Study of Brain Responses to Psychoactive Drugs. In: T. Ban, E. Shorter, D. Healy (Eds.):  History of CINP, IV: 661-672, 2004.


Galderisi S, Sannita WG. Pharmaco-EEG: A history of progress and missed opportunity. Clinical EEG and Neuroscience  37:61-65, 2006;


Fink M. Remembering the lost science of pharmaco-EEG. Acta psychiatr Scand.,  121:161-173. 2010


Methodology


Brazier MAB (Ed): Computer Techniques in EEG Analysis. EEG Journal, Supplement 20, 1-98, 1961.


Stille G, Herrmann W, Bente D, Fink M, Itil T, Koella WP, Kubicki S, Künkel H, Kugler J, Matejcek M, Petsche H. Guidelines for pharmaco-EEG studies in man. Pharmacopsychiatry 15:107-108;1982


Herrmann WM, Abt K, Coppola R, et al. International Pharmaco-EEG Group (IPEG). Recommendations for EEG and evoked potential mapping. Neuropsychobiology  22:170-176. 1989


Association or dissociation?


Wikler A.  Pharmacologic dissociation of behavior and EEG 'sleep patterns' in dogs: Morphine, n-allynormorphine and atropine. Proc Soc exp Biol 79:261-264, 1952;


Wikler A. Clinical and electroencephalographic studies on the effect of mescaline, n-allyInormorphine and morphine in man. J nerv ment Dis 120:157-175, 1954.


Fink M. EEG classification of psychoactive compounds in man: Review and theory of behavioral association. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967 U.S.G.P.O., Washington, D.C., 497-507, 1968;


Fink M., Itil T. Neurophysiology of the phantastica: EEG and behavioral relations in man. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. U.S.G.P.O., Washington, D.C., 1231-1239, 1968;


Fink M.  Itil T. EEG and human psychopharmacology: IV: Clinical antidepressants. In: Efron D, Cole JO, Levine J, Wittenborn JR. (Eds): Psychopharmacology: A Review of Progress 1957-1967. U.S.G.P.O., Washington, D.C., 671-682, 1968;


Fink M. EEG and human psychopharmacology.  Annu Rev Pharmacol 9:241-258, 1969;


Bradley P and Fink M. (Eds): Anticholinergic Drugs and Brain Functions in Animals and Man. Prog Brain Res 28, 184 pp., 1968.


Fink M. EEG and behavior: Association or dissociation in man? Integrative Psychiatry  9:108-123, 1993.


Examples of human studies.


Fink M, Kahn RL. Relation of EEG delta activity to behavioral response in electroshock: Quantitative serial studies. Arch Neurol & Psychiatry 78:516-525,1957


Fink M. Electroencephalographic  and behavioral effects of Tofranil. Canad Psychiat Assoc J, 4 (suppl) 166-71, 1959.


Itil TM, Polvan N, Hsu W. Clinical and EEG effects of GB-94, a tetracyclic antidepressant: EEG model in the discovery of a new psychotropic drug. Curr Ther Res 14:395-413, 1972.


Volavka J, Levine R, Feldstein S, Fink M. Short-term effects of heroin in man. Arch Gen Psychiatry 30:677-684,1974.


Itil TM, Cora R, Akpinar S, Herrmann WH, Patterson CJ. "Psychotropic" action of sex hormones:  Computerized EEG in establishing the immediate CNS effects of steroid hormones. Curr Therapeutic Res 16:1147-1170, 1974.


Fink M, Kety S, McGaugh J (Eds.): Psychobiology of Convulsive Therapy. Washington DC: VH Winston & Sons, 1974.


Volavka J, Fink M, Panayiotopoulos CP. Acute EEG effects of cannabis preparations in long-term users. In: C. Stefanis, R. Dornbush, M Fink (Eds): Hashish- A Study of Long-Term Use. NY: Raven Press, 1977.


American Psychiatric Association Electroconvulsive therapy. Task Force Report #14. Washington, DC: American Psychiatric Association. (1978). (200 pp.).


Fink M, Irwin P, Sannita W, Papakostas Y, Green MA. Phenytoin: EEG effects and plasma levels in volunteers. Therap Drug Monitoring 1: 93-104, 1979.


Fink M and Irwin P. EEG and behavioral profile of flutroline (CP-36,584), a novel antipsychotic drug. Psychopharmacology 72: 67-71, 1981.


Fink M and Irwin P. Pharmaco-EEG study of 6-azamianserin (ORG-3770): Dissociation  of EEG and pharmacologic predictors of antidepressant activity. Psychopharmacology 78: 44-48, 1982.


Fink M, Irwin P. CNS effects of acetylsalicylic acid (Aspirin). Clin Pharm Therap 32:362-365, 1982.


Additional notes.


This is a  list of  psychiatric medications  used by  psychiatrists  and other  physicians  to treat  mental illness  or distress.


The list is ordered alphabetically according to the condition or conditions, then by the  generic  name of each medication. The list is not exhaustive and not all drugs are used regularly in all countries. Some medications treat multiple conditions and appear multiple times.


The  psychopharmacology revolution  covers the introduction of various psychiatric drugs into clinical practice as well as their continued development. Although not exclusively limited to the 1950s period, the literature tends to suggest that this decade was a particularly fruitful time for  CNS  drug discovery and it has been referred to as a "golden era".


The history of  chlorpromazine  can be traced back to the work of  BASF  who were creating dyes at around the turn of the 20th century (c.f.  methylene blue ). It was found that attaching basic side chains to the tricyclic  phenothiazine  residue resulted in compounds that functioned as reliable  antihistamines .


Henri Laborit  was first using chlorpromazine to treat the anxiety of patients prior to surgery. He noted the so-called "indifference" that this agent causes and suggested that it be used on agitated psychotic patients. [ 1 ] [ 2 ]


Chlorpromazine has H1, M1, and α1 receptor antagonist activity. This causes sedation, anticholinergic effects, as well as orthostatic hypotension. It also functions as a blocker of D2 receptors, although it is much weaker and less selective than  haloperidol  in this respect. Blockade of the D2 receptors is thought to underlie the antipsychotic effect of the  typical antipsychotics . However, in the case of atypicals such as  clozapine  and  risperidone , blockade of 5HT2A receptors are thought to also account for an important part of their pharmacology.


Minor chemical manipulations in the chemical structure of chlorpromazine was used to create novel antipsychotic agents such as  thioridazine  and  fluoperazine .


Minor chemical manipulations in the structure of chlorpromazine led to the first  tricyclic antidepressant  (TCA),  imipramine  (Tofranil), whose structure is iminodibenzyl ( dibenzazepine ) based. [ 3 ]


Imipramine was first used on agitated psychotic patients, but it was shown that in the majority of cases their condition did not improve and actually worsened slightly. However, it was noted that a few of the patients who were depressed became more animated so its use in the treatment of depression became apparent.


Due to the chemical similarity of imipramine to chlorpromazine, this agent also functions as a H1, M1, and α1 receptor antagonist. Imipramine is also known to function as a fast sodium channel blocker, which is said to account for the cardiotoxicity of this agent. The collective effect of imipramine on these receptors is not thought to contribute to its therapeutic activity in the treatment of depression, although it is believed to account for mostly all of its side effects.


The usefulness of the TCAs in treating depression is thought to stem from their ability to inhibit the uptake of the neurotransmitters serotonin (5-HT) and noradrenaline (NA). It was proposed that designing agents that were more selective for 5-HT and/or NA would lower the incidence of side effects. This in turn has led to the development/discovery of the SSRIs and SNRIs.


The so-called golden era also covers the discovery of the first  monoamine oxidase inhibitor ,  iproniazid  (Marsilid), which is  hydrazine  based. Like imipramine, this also was used in the treatment of depression. [ 3 ]


Iproniazid  was the result of a failed medicinal chemistry attempt to improve on the anti-tubercular activity of  isoniazid . It was first given to patients with  tuberculosis  where a surprising but wholly unexpected improvement in mood was noticed.  Nathan Kline  coined the term "psychic energizer" to account for this effect and posited that they be used in the treatment of depression.


Iproniazid is no longer used because it caused an unacceptable incidence in  jaundice . Nevertheless, related agents such as  phenelzine  and  isocarboxazid  are still on the market.


In addition,  tranylcypromine  is a non-hydrazine containing irreversible inhibitor of MAO which is also available. [ citation needed ]


A limitation of these agents is their potential to cause hypertension so their safety is not guaranteed. However, it seems that the selective inhibitor of the B isoform of MAO, selegiline, is much less likely to cause hypertension.


The investigations into the mechanism of activity of these agents that followed their discovery led to the proposal of the " chemical imbalance " of  neurotransmitters  theory of mood disorders, which is supposed to account for the  pathophysiology  and/or  pathogenesis  of these states. It follows that these so-called "imbalances" can be corrected by the judicious application of appropriately selected  psychotropic  medication(s).


An excess of dopamine is cited as the cause of schizophrenia, [ 4 ]  whereas a deficiency of noradrenaline and serotonin were cited as the cause for depression.


The discovery of  reserpine  was also of great significance to the development of the monoamine amine theory of depression.


Prior to the introduction of these agents, the management of mental disorders in America relied mainly on " psychoanalytic " methods said to be deriving from a " Freudian " understanding of the subject area. [ 3 ] [ 5 ]  Apparently, there was great resistance to the use of medicine in the treatment of mental disorders prior to the 1950s. It is, however, known that various other agents including amphetamine and opium have documented use in the history of treating depression, [ 6 ] [ 7 ]  and that barbiturates, lithium salts, bromide salts, various  anticholinergic  alkaloids, as well as opium, were all used in the history of the treatment of schizophrenia. [ 8 ] [ 9 ]


A  reuptake enhancer  ( RE ), also sometimes referred to as a  reuptake activator , is a type of  reuptake modulator  which enhances the  plasmalemmal   transporter -mediated  reuptake  of a  neurotransmitter  from the  synapse  into the  pre-synaptic   neuron , leading to a decrease in the  extracellular   concentrations  of the neurotransmitter and therefore a decrease in  neurotransmission .


The  antidepressant   tianeptine  was once claimed to be a  (selective)  serotonin  reuptake enhancer  (SRE or SSRE), but the role of serotonin reuptake in its mechanism is doubtful. Tianeptine has no affinity for the  serotonin transporter , neither increases nor decreases extracellular levels of serotonin in  cortico - limbic  structures of conscious rats, and it didn't show any other long-term effect on the serotonin pathway. [ 1 ]  Ultimately, tianeptine was determined to be a selective mu opioid receptor agonist.


Coluracetam  is a choline-reuptake enhancer. [ 2 ]  The  flavone   luteoline  as well as some of its  derivatives  enhance the reuptake at the  dopamine transporter , [ 3 ] [ 4 ]  extracts of  Caulis Sinomenii  activate DA/NE transporters. [ 5 ]


The  Scandinavian College of Neuropsychopharmacology  ( SCNP ) is a Nordic  psychopharmacology  organisation. The SCNP publishes the journal,  Acta Neuropsychiatrica .


Stimulants  (also known as  central nervous system stimulants , or  psychostimulants , or colloquially as  uppers ) are a class of drugs that increase  alertness . They are used for various purposes, such as enhancing  attention ,  motivation ,  cognition ,  mood , and  physical performance . Some stimulants occur naturally, while others are exclusively synthetic. Common stimulants include  caffeine ,  nicotine ,  amphetamines ,  cocaine ,  methylphenidate , and  modafinil . Stimulants may be subject to varying forms of regulation, or outright prohibition, depending on jurisdiction.


Stimulants increase activity in the  sympathetic nervous system , either directly or indirectly. Prototypical stimulants increase synaptic concentrations of  excitatory neurotransmitters , particularly  norepinephrine  and  dopamine  (e.g., methylphenidate). Other stimulants work by binding to the  receptors  of excitatory neurotransmitters (e.g., nicotine) or by blocking the activity of endogenous agents that promote sleep (e.g., caffeine). Stimulants can affect various functions, including  arousal ,  attention , the  reward system ,  learning ,  memory , and  emotion . Effects range from mild stimulation to  euphoria , depending on the specific drug, dose, route of administration, and inter-individual characteristics.


Stimulants have a long history of use, both for medical and non-medical purposes. Archeological evidence from Peru shows that cocaine use dates back as far as 8000 B.C.E. [ 1 ]  Stimulants have been used to treat various conditions, such as  narcolepsy ,  attention deficit hyperactivity disorder  (ADHD),  obesity ,  depression , and  fatigue . They have also been used as  recreational drugs ,  performance-enhancing substances , and  cognitive enhancers , by various groups of people, such as students, athletes, artists, and workers. They have also been used to promote aggression of combatants in wartime, both historically and in the present day. [ 2 ] [ 3 ] [ 4 ]


Simulants have potential risks and side effects, such as  addiction ,  tolerance ,  withdrawal ,  psychosis ,  anxiety ,  insomnia ,  cardiovascular problems , and  neurotoxicity . The misuse and abuse of stimulants can lead to serious health and social consequences, such as  overdose ,  dependence ,  crime , and  violence . Therefore, the use of stimulants is regulated by laws and policies in most countries, and requires medical supervision and prescription in some cases.


A  stimulant  is an overarching term that covers many  drugs  including those that increase the activity of the  central nervous system  and the body, [ 5 ]  drugs that are pleasurable and invigorating, or drugs that have  sympathomimetic  effects. [ 6 ]  Sympathomimetic effects are those effects that mimic or copy the actions of the  sympathetic nervous system . The sympathetic nervous system is a part of the nervous system that prepares the body for action, such as increasing the heart rate, blood pressure, and breathing rate. Stimulants can activate the same receptors as the natural chemicals released by the sympathetic nervous system (namely  epinephrine  and  norepinephrine ) and cause similar effects. [ 7 ]


Stimulants in therapeutic doses, such as those given to patients with  attention deficit hyperactivity disorder  (ADHD), increase ability to focus, vigor, sociability, libido and may elevate mood. However, in higher doses, stimulants may actually decrease the ability to focus, a principle of the  Yerkes-Dodson Law . [ 8 ]  In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep.


Many, but not all, stimulants have  ergogenic  effects; that is, they enhance physical performance. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect. [ 9 ]


Neurocognitive enhancing effects of stimulants, specifically  modafinil , amphetamine and methylphenidate have been reported in healthy adolescents by some studies, [ 10 ]  and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying. [ 10 ]  Still, results of these studies is inconclusive: assessing the potential overall neurocognitive benefits of stimulants among healthy youth is challenging due to the diversity within the population, the variability in cognitive task characteristics, and the absence of replication of studies. [ 10 ]  Research on the cognitive enhancement effects of modafinil in healthy non-sleep-deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions while others show no significant benefits or even a decline in cognitive functions. [ 11 ] [ 12 ] [ 13 ]


In some cases, psychiatric phenomena may emerge such as  stimulant psychosis ,  paranoia , and  suicidal ideation . Acute toxicity has been reportedly associated with hyperhydrosis, panic attacks, severe anxiety, mydriasis, paranoia, aggressive behavior, excessive motor activity, psychosis, rhabdomyolysis,  and  punding . The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia. [ 14 ]  Most drugs classified as stimulants are  sympathomimetic , meaning that they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such as  mydriasis  (dilation of the pupils), increased heart rate, blood pressure, respiratory rate and body temperature. [ 6 ]  When these changes become pathological, they are called  arrhythmia ,  hypertension , and  hyperthermia , and may lead to  rhabdomyolysis ,  stroke ,  cardiac arrest , or  seizures . However, given the complexity of the mechanisms that underlie these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal. [ 15 ]


Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, but found a correlation between prescription stimulant use and  ischemic   heart attacks . [ 16 ]   A review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer-term studies. [ 17 ]  A review of a year long period of prescription stimulant use in those with  ADHD  found that cardiovascular side effects were limited to transient increases in blood pressure only. [ 18 ]  However, a 2024 systematic review of the evidence found that stimulants overall improve ADHD symptoms and broadband behavioral measures in children and adolescents, though they carry risks of side effects like appetite suppression and other adverse events. [ 19 ]  Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, and appears to be relatively safe. [ 20 ]


Abuse of prescription stimulants (not following physician instruction) or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of cardiorespiratory disease,  stroke , and  sepsis . [ 21 ]  Some effects are dependent upon the route of administration, with intravenous use associated with the transmission of many disease such as  Hepatitis C ,  HIV/AIDS  and potential medical emergencies such as  infection ,  thrombosis  or  pseudoaneurysm , [ 22 ]  while inhalation may be associated with increased  lower respiratory tract infection ,  lung cancer , and pathological restricting of lung tissue. [ 23 ]  Cocaine may also increase risk for autoimmune disease [ 24 ] [ 25 ] [ 26 ]  and damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, resulting in an increased risk for  Parkinson's disease . [ 27 ] [ 28 ] [ 29 ] [ 30 ]


Stimulants are widely used throughout the world as  prescription medicines  as well as without a prescription (either legally or  illicitly ) as  performance-enhancing  or  recreational  drugs. Among narcotics, stimulants produce a noticeable crash or  comedown  at the end of their effects. In the US, the most frequently prescribed stimulants as of 2013 were  lisdexamfetamine  (Vyvanse),  methylphenidate  (Ritalin), and  amphetamine  (Adderall). [ 31 ]  It was estimated in 2015 that the percentage of the world population that had used  cocaine  during a year was 0.4%. For the category "amphetamines and prescription stimulants" (with "amphetamines" including  amphetamine  and  methamphetamine ) the value was 0.7%, and for  MDMA  0.4%. [ 32 ]


Stimulants have been used in medicine for many conditions including  obesity ,  sleep disorders ,  mood disorders ,  impulse control disorders ,  asthma ,  nasal congestion  and, in case of cocaine, as  local anesthetics . [ 33 ]   Drugs used to treat obesity are called  anorectics  and generally include drugs that follow the general definition of a stimulant, but other drugs such as  cannabinoid receptor antagonists  also belong to this group. [ 34 ] [ 35 ]   Eugeroics  are used in management of sleep disorders characterized by  excessive daytime sleepiness , such as  narcolepsy , and include stimulants such as  modafinil  and  pitolisant . [ 36 ] [ 37 ]  Stimulants are used in impulse control disorders such as  ADHD [ 38 ]  and  off-label  in  mood disorders  such as  major depressive disorder  to increase  energy , focus and elevate mood. [ 39 ]   Stimulants such as  epinephrine , [ 40 ]   theophylline  and  salbutamol [ 41 ]  orally have been used to treat asthma, but inhaled  adrenergic drugs  are now preferred due to less systemic side effects.  Pseudoephedrine  is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection. [ 42 ] [ 43 ]


Stimulants were one of the first classes of drugs to be used in the treatment of  depression , beginning after the introduction of the amphetamines in the 1930s. [ 44 ] [ 45 ] [ 46 ]  However, they were largely abandoned for treatment of depression following the introduction of conventional  antidepressants  in the 1950s. [ 44 ] [ 45 ]  Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years. [ 47 ] [ 48 ]


Stimulants produce a fast-acting and pronounced but transient and short-lived  mood lift . [ 49 ] [ 50 ] [ 47 ] [ 45 ]  In relation to this, they are minimally effective in the treatment of depression when administered continuously. [ 49 ] [ 50 ]  In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and  dependence . [ 48 ]  Although the efficacy for depression with continuous administration is modest, it may still reach  statistical significance  over  placebo  and provide benefits similar in magnitude to those of conventional antidepressants. [ 51 ] [ 52 ] [ 53 ] [ 54 ]  The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid  tolerance . [ 49 ] [ 50 ] [ 45 ] [ 55 ]  Tolerance to the effects of stimulants has been studied and characterized both in animals [ 55 ] [ 56 ] [ 57 ] [ 58 ]  and humans. [ 59 ] [ 60 ] [ 61 ] [ 62 ]  Stimulant  withdrawal  is remarkably similar in its symptoms to those of  major depressive disorder . [ 63 ] [ 55 ] [ 64 ] [ 65 ]


Classifying stimulants is difficult, because of the large number of classes the drugs occupy, and the fact that they may belong to multiple classes; for example,  ecstasy  can be classified as a  substituted methylenedioxyphenethylamine , a  substituted amphetamine  and consequently, a  substituted phenethylamine . [ citation needed ]


Major stimulant classes include  phenethylamines  and their daughter class  substituted amphetamines . [ 66 ] [ 67 ]


Substituted amphetamines  are a  class of compounds  based upon the  amphetamine  structure; [ 68 ]  it includes all  derivative  compounds which are formed by replacing, or  substituting , one or more  hydrogen atoms  in the amphetamine core structure with  substituents . [ 68 ] [ 69 ] [ 70 ]  Examples of substituted amphetamines are amphetamine (itself), [ 68 ] [ 69 ]   methamphetamine , [ 68 ]   ephedrine , [ 68 ]   cathinone , [ 68 ]   phentermine , [ 68 ]   mephentermine , [ 68 ]   bupropion , [ 68 ]   methoxyphenamine , [ 68 ]   selegiline , [ 68 ]   amfepramone , [ 68 ]   pyrovalerone , [ 68 ]   MDMA  (ecstasy), and  DOM  (STP). Many drugs in this class work primarily by activating  trace amine-associated receptor 1  (TAAR1); [ 71 ]  in turn, this causes  reuptake inhibition  and effluxion, or release, of  dopamine ,  norepinephrine , and  serotonin . [ 71 ]  An additional mechanism of some substituted amphetamines is the release of  vesicular stores  of  monoamine neurotransmitters  through  VMAT2 , thereby increasing the concentration of these neurotransmitters in the  cytosol , or intracellular fluid, of the  presynaptic neuron . [ 72 ]


Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat  major depression , where subjects do not respond well to traditional  SSRI  medications, [ citation needed ]  but evidence supporting this use is poor/mixed. [ 48 ]  Notably, two recent large  phase III  studies of  lisdexamfetamine  (a  prodrug  to amphetamine) as an adjunct to an  SSRI  or  SNRI  in the treatment of  major depressive disorder  showed no further benefit relative to  placebo  in effectiveness. [ 73 ]  Numerous studies have demonstrated the effectiveness of drugs such as  Adderall  (a mixture of  salts  of  amphetamine  and  dextroamphetamine ) in controlling symptoms associated with  ADHD . Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse. [ 74 ]


Hundreds of cocaine analogs have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of a  tropane . Various modifications include substitutions on the  benzene ring , as well as additions or substitutions in place of the normal carboxylate on the tropane 2 carbon. Various compound with similar structure activity relationships to cocaine that aren't technically analogs have been developed as well.


Most stimulants exert their activating effects by enhancing  catecholamine  neurotransmission. Catecholamine neurotransmitters are employed in regulatory pathways implicated in attention, arousal, motivation, task salience and reward anticipation. Classical stimulants either  block the reuptake  or  stimulate the efflux  of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those with  empathogenic  and  hallucinogenic  effects, also affect  serotonergic  transmission. Some stimulants, such as some amphetamine derivatives [ which? ]  and, notably,  yohimbine , can decrease  negative feedback  by antagonizing regulatory  autoreceptors . [ 75 ]   Adrenergic agonists , such as, in part,  ephedrine , act by directly binding to and activating  adrenergic receptors , producing sympathomimetic effects. [ citation needed ]


There are also more indirect  mechanisms of action  by which a drug can elicit activating effects. Caffeine is an  adenosine receptor antagonist , and only indirectly increases catecholamine transmission in the brain. [ 76 ]   Pitolisant  is an  histamine 3 (H 3 )-receptor inverse agonist . As  histamine 3 (H 3 ) receptors  mainly act as  autoreceptors , pitolisant decreases negative feedback to  histaminergic  neurons, enhancing histaminergic transmission.


The precise  mechanism of action  of some stimulants, such as modafinil, for treating symptoms of narcolepsy and other sleep disorders, remains unknown. [ 77 ] [ 78 ] [ 79 ] [ 80 ] [ 81 ]