Antipsychotics (also called neuroleptics) are a group of psychoactive drugs commonly but not exclusively used to treat psychosis,[1] which is typified by schizophrenia. Over time a wide range of antipsychotics have been developed. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s. Most of the drugs in the second generation, known as atypical antipsychotics, have more recently been developed, although the first atypical anti-psychotic, clozapine, was discovered in the 1950s, and introduced clinically in the 1970s. Both classes of medication tend to block receptors in the brain's dopamine pathways, but antipsychotic drugs encompass a wide range of receptor targets. A number of side effects have been observed in relation to specific medications, including weight gain, agranulocytosis, tardive dyskinesia, tardive akathisia, tardive psychoses and tardive dysphrenia. The development of new antipsychotics, and the relative efficacy of different ones, is an important ongoing field of research. Antipsychotic medication is not generally regarded as a good treatment, just the best available. The most appropriate drug for an individual patient requires careful consideration.
Terminology
Antipsychotics are also referred to as neuroleptic drugs.[2] The word neuroleptic is derived from Greek: "νεύρον" (originally meaning sinew but today referring to the nerves) and "λαμβάνω" (meaning take hold of). Thus, the word means taking hold of one's nerves. This term reflects the drugs' ability to make movement more difficult and sluggish, which clinicians previously believed indicated that a dose was high enough.[citation needed] The lower doses used currently have resulted in reduced incidence of motor side effects and sedation,[citation needed] and the term is less commonly used than in the past.[citation needed]
Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or second-generation antipsychotics. The typical antipsychotics are classified according to their chemical structure while the atypical antipsychotics are classified according to their pharmacological properties. These include serotonin-dopamine antagonists (see dopamine antagonist and serotonin antagonist), multi-acting receptor-targeted antipsychotics (MARTA, those targeting several systems), and dopamine partial agonists, which are often categorized as atypicals.[3]
Typical antipsychotics are also sometimes referred to as tranquilizers,[4] because some of them can tranquilize and sedate. This term is increasingly disused, as the terminology implies a connection with benzodiazepines ("minor" tranquilizers) when none exists.[citation needed]
Usage
Common conditions with which antipsychotics might be used include schizophrenia, mania, and delusional disorder. They might be used to counter psychosis associated with a wide range of other diagnoses, such as psychotic depression. In addition, these drugs are used to treat non-psychotic disorders. For example, some antipsychotics (haloperidol, pimozide) are used off-label to treat Tourette syndrome, whereas aripiprazole is prescribed in some cases of Asperger's syndrome.
Although atypical antipsychotics are generally considered to be more effective and to have reduced side-effects compared to typical antipsychotics, this view has been challenged.[5] Clozapine appears to be more effective than other atypical antipsychotics.[3][6] However, when controlling for dose differences, the differences in efficacy and side-effects between atypical and typical antipsychotics were significantly reduced. One review has concluded there were no differences[3] while another[7] found that atypicals were "only moderately more efficacious," and that only clozapine has a lower probability of extrapyramidal symptoms.[3] These conclusions were, however, questioned by another review, which found that clozapine, amisulpride, and olanzapine and risperidone were more effective.[3][8]
History
The original antipsychotic drugs were happened upon largely by chance and were tested empirically for their effectiveness. The first antipsychotic was chlorpromazine, which was developed as a surgical anesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a "chemical lobotomy". Lobotomy was used to treat many behavioral disorders, including psychosis, although its "effectiveness" was (from a modern viewpoint) due to its tendency to markedly reduce behavior of all types. However, chlorpromazine quickly proved to reduce the effects of psychosis in a more effective and specific manner than the extreme lobotomy-like sedation it was known for.
The underlying neurochemistry involved has since been studied in detail, and subsequent anti-psychotic drugs have been discovered by an approach that incorporates this sort of information.
Common antipsychotics
Commonly used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.
First generation antipsychotics
Butyrophenones
Main article:
Butyrophenones
Phenothiazines
Main article:
Phenothiazines
Thioxanthenes
Main article:
Thioxanthenes
Second generation antipsychotics
- Clozapine (Clozaril) - Requires weekly to biweekly complete blood count due to risk of agranulocytosis.
- Olanzapine (Zyprexa) - Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder. Dosing 2.5 to 20 mg per day.
- Risperidone (Risperdal) - Dosing 0.25 to 6 mg per day and is titrated upward; divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndrome and anxiety disorder.
- Quetiapine (Seroquel) - Used primarily to treat bipolar disorder and schizophrenia, and "off-label" to treat chronic insomnia and restless legs syndrome; it is a powerful sedative. Dosing starts at 25 mg and continues up to 800 mg maximum per day, depending on the severity of the symptom(s) being treated.
- Ziprasidone (Geodon) - Approved in 2006[citation needed] to treat bipolar disorder. Dosing 20 mg twice daily initially up to 80 mg twice daily. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval.
- Amisulpride (Solian) - Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic patients, leading to its use in dysthymia and social phobias. Amisulpride has not been approved for use by the Food and Drug Administration in the United States.
- Asenapine is a 5-HT2A- and D2-receptor antagonist under development for the treatment of schizophrenia and acute mania associated with bipolar disorder.
- Paliperidone (Invega) - Derivative of risperidone that was approved in 2006.
- Zotepine (Nipolept, Losizopilon, Lodopin, Setous)- An atypical antipsychotic indicated for acute and chronic schizophrenia. It was approved in Japan circa 1982 and Germany in 1990, respectively.
Third generation antipsychotics
- Aripiprazole (Abilify) - Dosing 1 mg up to maximum of 30 mg has been used. Mechanism of action is thought to reduce susceptibility to metabolic symptoms seen in some other atypical antipsychotics.[9]
- Partial agonists of dopamine
- Under clinical development - Bifeprunox; norclozapine (ACP-104).
Other options
- Tetrabenazine is similar in function to antipsychotic drugs, though is not, in general, considered an antipsychotic itself. Its main usefulness is the treatment of hyperkinetic movement disorders such as Huntington's disease and Tourette syndrome, rather than for conditions such as schizophrenia. Also, rather than having the potential to cause tardive dyskinesia, which most antipsychotics have, tetrabenazine can be an effective treatment for the condition.
- Cannabidiol - One of the main psychoactive components of cannabis. A recent study has shown that cannabidiol may be as effective as atypical antipsychotics in treating schizophrenia,[10] although its use for this purpose has not yet been widely accepted.
The most common typical antipsychotic drugs are now off-patent, meaning any pharmaceutical company is legally allowed to produce generic versions of these medications. While this makes them cheaper than the atypical drugs that are still manufactured under patent constraints, atypical drugs are preferred as a first-line treatment because they are believed to have fewer side effects[citation needed] and seem to have additional benefits for the 'negative symptoms'[citation needed] of schizophrenia.
Metabotropic glutamate receptor 2 agonism has been seen as a promising strategy in the development of novel antipsychotics.[11][12][13] When tested in patients, the research substance LY2140023 yielded promising results and had few side effects. The active metabolite of this prodrug targets the brain glutamate receptors mGluR2/3 rather than dopamine receptors.[14]
Drug action
All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine receptors in this pathway that is thought to control psychotic experiences.
Typical antipsychotics are not particularly selective and also block Dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some of the unwanted side effects that the typical antipsychotics can produce (see below). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than low-potency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side effects.
Atypical antipsychotic drugs have a similar blocking effect on D2 receptors. Some also block or partially block serotonin receptors (particularly 5HT2A, C and 5HT1A receptors):ranging from risperidone, which acts overwhelmingly on serotonin receptors, to amisulpride, which has no serotonergic activity. The additional effects on serotonin receptors may be why some of them can benefit the 'negative symptoms' of schizophrenia.[15]
Side effects
Antipsychotics are associated with a range of side effects. It is well-recognized that many stop taking them (around two-thirds of people in controlled drug trials) due in part to adverse effects.[16] Extrapyramidal reactions include acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, intense dreams or nightmares, and hyperprolactinaemia.[17]
From a subjective perspective, antipsychotics heavily influence one's perceptions of pleasurable sensations, causing a severe reduction in feelings of desire, motivation, pensive thought, and awe. This does not coincide with the apathy and lack of motivation experienced by the negative symptoms of schizophrenia. Detrimental effects on short term memory, which affect the way one figures and calculates (although this also may be purely subjective), may also be observed on high enough dosages. These are all the reasons why they are thought to affect "creativity". Also, for some individuals with schizophrenia, too much stress may cause "relapse".
Following are details concerning some of the side effects of antipsychotics:
- Antipsychotics, particularly atypicals, appear to cause diabetes mellitus and fatal diabetic ketoacidosis, especially (in US studies) in African Americans.[18][19]
- Antipsychotics may cause pancreatitis.[20]
- The atypical antipsychotics (especially olanzapine) seem to cause weight gain more commonly than the typical antipsychotics. The well-documented metabolic side effects associated with weight gain include diabetes, which can be life-threatening.
- Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is in no danger.[citation needed]
- One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements often of the lips, face, legs, or torso. It is believed that there is a greater risk of developing tardive dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder.
- A potentially serious side effect of many antipsychotics is that they tend to lower an individual's seizure threshold. Chlorpromazine and clozapine, in particular, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions such as epilepsy, or brain damage.
- Deterioration of teeth due to a lack of saliva.[citation needed]
- Neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency, as the patient's temperature suddenly increases to dangerous levels.
- Dysphoria.
- Following controversy over possible increased mortality (death) related to antipsychotics in indivdiuals with dementia, warnings have been added to packaging.[21]
Some people suffer few apparent side effects from taking antipsychotic medication, whereas others may have serious adverse effects. Some side effects, such as subtle cognitive problems, may go unnoticed.
There is a possibility that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benzatropine, although this remains to be established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.
Structural effects
Many studies now indicate that chronic treatment with antipsychotics affects the brain at a structural level, for example increasing the volume of the basal ganglia (especially the caudate nucleus), and reducing cortical grey matter volume in different brain areas. The effects may differ for typical versus atypical antipsychotics and may interact with different stages of disorders.[22] Death of neurons in the cerebral cortex, especially in women, has been linked to the use of both typical and atypical antipsychotics for individuals with Alzheimers.[23]
Recent studies on macaque monkeys have found that administration of haloperidol or olanzapine for about two years led to a significant overall shrinkage in brain tissue,[24] in both gray and white matter across several brain areas, with lower glial cell counts,[25] due to a decrease in astrocytes and oligodendrocytes,[26] and increased neuronal density. It has been said that these studies require serious attention and that such effects were not clearly tested for by pharmaceutical companies prior to obtaining approval for placing the drugs on the market.[27]
Efficacy
There have been a large number of studies of the efficacy of typical antipsychotics, and an increasing number on the more recent atypical antipsychotics.
The American Psychiatric Association and the UK National Institute for Health and Clinical Excellence recommend antipsychotics for managing acute psychotic episodes and for preventing relapse.[28][29] They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible.
Antipsychotic polypharmacy—prescribing two or more antipsychotics at the same time for an individual—is said to be a frequent practice but not necessarily evidence-based.[30]
Some doubts have been raised about the long-term effectiveness of antipsychotics because two large international World Health Organization studies found individuals diagnosed with schizophrenia tend to have better long-term outcomes in developing countries (where there is lower availability and use of antipsychotics) than in developed countries.[31][32] The reasons for the differences are not clear, however, and various explanations have been suggested.
Some argue that the evidence for antipsychotics from withdrawal-relapse studies may be flawed, because they do not take into account that antipsychotics may sensitize the brain and provoke psychosis if discontinued.[33] Evidence from comparison studies indicates that at least some individuals recover from psychosis without taking antipsychotics, and may do better than those that do take antipsychotics.[34] Some argue that, overall, the evidence suggests that antipsychotics only help if they are used selectively and are gradually withdrawn as soon as possible.[35]
A dose response effect has been found in one study from 1971 between increasing neuroleptic dose and increasing number of psychotic breaks.[36][verification needed]
Prevalence of use
A large proportion of the population may be prescribed antipsychotic medications. It is estimated that the prevalence of schizophrenia is around 0.55% of the population.[37] Similarly, the prevalence of bipolar disorder is estimated at around 2%[38] (and around 8-12% for major depressive disorder).[39][40]
Typical versus atypical
While the atypical, second-generation medications were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extra-pyramidal symptoms in particular) than typical medications, the results showing these effects often lack robustness. To remediate this problem, the NIMH conducted a recent multi-site, double-blind study (the CATIE project), which was published in 2005.[41] This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1493 persons with schizophrenia. Perphenazine was chosen because of its lower potency and moderate side effect profile. The study found that only olanzapine outperformed perphenazine in the researchers' principal outcome, the discontinuation rate. The authors also noted the apparent superior efficacy of olanzapine to the other drugs for greater reduction in psychopathology, longer duration of successful treatment, and lower rate of hospitalizations for an exacerbation of schizophrenia. In contrast, no other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on those measures. Olanzapine, however, was associated with relatively severe metabolic effects: Subjects with olanzapine showed a major weight gain problem and increases in glucose, cholesterol, and triglycerides. The average weight gain (1.1 kg/month, or 44 pounds for the 18 months that the study lasted) casts serious doubt on the potentiality of long-term use of this drug. Perphenazine did not create more extrapyramidal side effects as measured by rating scales (a result supported by a meta-analysis by Dr. Leucht published in Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8 percent vs. 2 percent to 4 percent, P=0.002).
A phase 2 part of this study roughly replicated these findings.[42] This phase consisted of a second randomization of the patients that discontinued taking medication in the first phase. Olanzapine was again the only medication to stand out in the outcome measures, although the results did not always reach statistical significance, due in part to the decrease of power. Perphenazine again did not create more extrapyramidal effects.
A subsequent phase was conducted. [43] This phase allowed clinicians to offer clozapine which was more effective at reducing medication drop-outs than other neuroleptic agents. However, the potential for clozapine to cause toxic side effects, including agranulocytosis, limits its usefulness.
Over-prescribing
Use of this class drugs has a history of criticism in residential care. As the drugs use can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff.[44]
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