TYPES OF ANTIPSYCHOTICS AND THEIR TYPICAL SIDE EFFECTS IN HUMANS



Antipsychotic medications are generally divided into two categories: first generation (typical) and second generation (atypical). The main difference between the two types of antipsychotics is that the first generation drugs block dopamine and the second generation drugs block dopamine and also affect serotonin levels. Evidence suggests that some of the second generation drugs have milder movement- related side-effects than the first generation drugs.
Both categories of drugs work equally well overall, although no drug or type of drug works equally well for everyone who takes it. When the same drug is given to a group of people, one third of that group will find that it works well; another third will find that the drug helps only with some symptoms; and the final third will find that it does not help at all. For this reason, people may need to try different antipsychotics before finding the one that works best for them.
Most of these drugs are given in tablet form, some are liquids and others are given as injections. Some are available as long-lasting (depot) injections, which may be given anywhere from once a week to once a month.
Antipsychotics are often used in combination with other medications to treat other symptoms of mental health problems or to offset side-effects.
Most people who take antipsychotics over a longer term are now prescribed the second generation (also called atypical) drugs.
2.1       Second generation (atypical) antipsychotics
Medications available in this class include risperidone (Risperdal)*, quetiapine (Seroquel), olanzapine (Zyprexa), ziprasidone (Zeldox), paliperidone (Invega), aripiprazole (abilify) and clozapine (clozaril). clozapine is exceptional in that it often works even when other medications have failed; however, because it requires monitoring of white blood cell counts, it is not the first choice for treatment. The second generation antipsychotics are usually the first choice for the treatment of schizophrenia. Although they may not be officially approved for these other uses, they are sometimes used in the treatment of mood and anxiety disorders, such as bipolar, posttraumatic stress and obsessive-compulsive disorders.
Some possible side-effects of this type of medication include dry mouth, dizziness, blurred vision and, rarely, seizures. The following table lists other side-effects of second generation antipsychotics and shows which drugs are most likely to least likely to have these effects.
*medications are referred to in two ways: by their generic name and
by their brand or trade names. Brand names available in Canada appear here in brackets.

Table: showing the side effect of second generation antipsychotics
Side-effects of second generation antipsychotics
Drugs most likely to least likely to have these effects
Weight gain, diabetes
clozapine > olanzapine > quetiapine > risperidone > ziprasidone, aripiprazole
movement effects (e.g., tremor, stiffness, agitation)
risperidone > olanzapine, quetiapine, ziprasidone, aripiprazole > clozapine
Sedation (e.g., sleepiness, low energy)
clozapine, olanzapine and quetiapine > risperidone, ziprasidone, aripiprazole
Decreased sex drive and function, missed periods, discharge from breasts
risperidone > olanzapine, quetiapine > clozapine, ziprasidone

2.1.1    Side-effects of the typical antipsychotics
Most of the side effects of the typical antipsychotics can also be encountered with the atypical agents; however, they are less frequent and generally less severe.
Weight gain is problem in schizophrenia and other mental disorders, in part, because of poor eating habits and lack of exercise. However, the atypical antipsychotics exacerbate this problem. A meta-analysis (Allison and Casey, 2001) estimated that over a 10 week period the mean increase was as follows:
1) clozapine 4.45 kg
2) olanzapine 4.15 kg
3) risperidone 2.1 kg (quetiapine probably similar)
4) ziprasidone 0.04 kg (aripiprazole probably similar).
The prevalence of type 2 diabetes in people with schizophrenia is double that of the general population. Over recent years there has been concern this may be a direct result of atypical antipsychotic treatment. As the atypical antipsychotics are the most effective component in the medical management of psychotic disorders, this question was soberly examined. An association between schizophrenia and diabetes has been recognized for over a century. Risk factors for diabetes include poor overall health, lifestyle and level of access to heath care. Atypical antipsychotics are associated with weight gain, but there is no evidence for an intrinsic role for the antipsychotics in the aetiology of diabetes.
As this issue has been brought to the attention of clinicians, they have a responsibility to monitor the diabetes risk factors of patients (Poulin et al, 2005).
Hyperlipidemia (raised cholesterol and triglycerides) appears to be associated with the dibenzodiazepine-derived antipsychotics (clozapine, olanzapine and quetiapine).
QTc interval prolongation has been a matter of concern. The average QTc interval in healthy adults is about 400 msec, and a QTc interval of 500 msec or more is a risk factor for torsade de pointes (a ventricular arrhythmia which can lead to syncope, ventricular fibrillation and sudden death). One study found the following prolongations:
1) ziprasidone 20.3 ms
2) quetiapine 14.5 ms
3) risperidone 11.6 ms
4) olanzapine 6.8 ms
5) haloperidol 4.7 ms
Myocarditis and cardiomyopathy are rare (0.015-0.188 %; Merrill et al, 2005) side effects of clozapine therapy.
Recommendations for the monitoring/management of the side effects of the atypical antipsychotics have been provided (Marder et al, 2004). However, further work is required. When weight gain is anticipated (clozapine, olanzapine, quetiapine and risperidone) weight and BMI should be recorded. Nutritional and life style (exercise) advice is recommended. With excessive weight gain a change to another agent may be considered. When diabetes is anticipated (clozapine and olanzapine in particular) the weight is to be monitored and laboratory measures (eg fasting blood glucose) are indicated. When hyperlipidemia is anticipated (clozapine, olanzapine and quetiapine) serum cholesterol and triglycerides may be monitored. When QTC prolongation is anticipated (ziprasidone, particularly), EEG monitoring is recommended in cases of increased cardiac risk (known heart disease, syncope, family history of early sudden death). Myocarditis has been associated with clozapine and clozapine clinics have specialized screening procedures.
2.1.2    Individual atypical antipsychotics
As in all branches of medicine, if a disorder cannot be controlled with standard doses of a particular agent, first the dose is increased judiciously, and if the desired result remains evasive, another agent is trialled. The management of psychosis is difficult. Fortunately we have a range of atypical antipsychotics; while they have some similar actions, they come from range chemical classes, and all have particular advantages. A series of trials may be necessary for the best possible outcome.
Clozapine:      Clozapine is often effective in treating schizophrenia which has been unresponsive to all other antipsychotics. It is unique in causing neutropenia (potentially fatal) in 1-2% of patients. Thus, clozapine is reserved for severe otherwise unresponsive psychosis, and must be managed by specialized clinics which conduct regular (weekly for the first 18 weeks) blood tests.
Other side-effects include significant weight gain, hypotension and tachycardia. Hypersalivation (unknown with the typical antipsychotics) can be troublesome with clozapine (and rarely with some other atypicals, such as olanzapine). 1% of patients experience seizures – this does not mean clozapine must be ceased – instead, anticonvulsants are added. This is a formidable array of side-effects; nevertheless the antipsychotic benefits are substantial. Clozapine is also useful in the treatment of TD.
Risperidone:  Risperidone is an effective antipsychotic. At high doses (8 mg and above) it loses some of its advantages over typical antipsychotics, insofar, as acute EPS readily appear. A major disadvantage is the elevation of prolactin levels. A preparation which dissolves in the mouth is available. Risperidone has an advantage over the other atypicals in that an IMI depot (long-acting) preparation is available. This can be administered once per fortnight during the maintenance phase, somewhat reducing compliance problems.
Paliperidone: Paliperidone is the active metabolite of risperidone, which was released when the patent of the parent chemical was about to expire. It has a slightly improved side-effect profile. There is less weight gain, but more EPS problems, and the elevation of prolactin remains problematic. The dosing strategy is simple; one capsule enables a single daily dose.
Recently a paliperidone depot has become available which need only be repeated monthly (a great advantage over 2/52 injection). The monthly dose is usually 25-50 mg.
Olanzapine:    Olanzapine is an effective antipsychotic which has gained acceptance as a mood stabilizer (used in the prophylaxis of mood disorder; Tohen et al, 2005). It has a pharmacological action and side-effect profile similar to clozapine (except, it is not associated with blood dyscrasia). The most troublesome side-effects are weight gain and sedation. The risks of diabetes and hyperlipidemia need to be monitored. An occasional side-effect, which is seen more regularly with clozapine, is hypersalivation. Olanzapine does not elevate prolactin to a significant degree. The sedating/calming effect of olanzapine is useful in acute disturbance. Olanzapine has an advantage of over the other atypical medications in being available in an IMI form for acute administration. A preparation which dissolves in the mouth is available. A long-acting depot form is available but because physiological response is variable, the patient must be observed for 3 hours following every injection (which is proving to be a disincentive).
Quetiapine:    Quetiapine is an effective antipsychotic which has a receptor binding profile similar to clozapine, but with relatively lower affinity for all receptors. The side-effect profile is favourable, 75% of respondents denying any side-effects. Sedation and hypotension are reported, especially during the commencement phase. Weight gain, and the risk of diabetes and hyperlipidemia need to be considered. Quetiapine has little affinity for muscarinic receptors so that blurred vision and difficulty with micturition are rarely problems. The rate of EPS is similar to placebo and there is no significant elevation of prolactin. Quetiapine may cause sedation and weight gain. (Komossa et al, 2009).
Amisulpride:  Amisulpride is a useful antipsychotic which has effects (potent antagonist) only at D2 and D3 receptors (and no effect on serotonin receptors). At recommended doses it appears to be selective for limbic (rather than extra-pyramidal system) receptors (Xiberas et al, 2001). Unfortunately, when higher doses are required, EPS side-effects may become a problem. Amisulpride is less likely to cause weight gain than the other atypical antipsychotics, but it produces robust elevation of prolactin levels, thus breast development and lactation in both men and women and amenorrhoea in women may be bothersome side effects. (Komossa et al, 2009).
Aripiprazole: Aripiprazole is a recently released antipsychotic. Rather than an antagonist of dopamine receptors, it appears to be a high affinity partial agonist at presynaptic D2 receptors and an antagonist at postsynaptic D2 receptors. It has little affinity for D3, D4 and D1-like receptors, and its affinity for 5HT-2A receptors is low. There is some alph-1 blockade and orthostatic hypotension has been reported. The efficacy appears similar to risperidone and less than olanzapine, but the side-effect profile appears favourable at manufacturer recommended doses, with minimal elevation of prolactin. (Komossa et al, 2009).
However, a recent review demonstrated no clear advantage over many other second generation antipsychotics (Khanna et al, 2013).  Aripiprazole has a role as a mood stabilizer (Keck et al, 2007).
Asenopine:     Is a recently released second generation antipsychotic, unique in being administered sub-lingualy. It appears to be an effective antipsychotic (compared to the other available agents – but, none of them are much good). It has a lower profile of weight gain and adverse changes in glycemic or lipid profile (Bobo, 2013), which will be considered an advantage. However, dose related akathisia and oral hypoaesthesia, my be problematic.

2.2       First generation (typical) antipsychotics
These older medications include chlorpromazine (once marketed as Largactil), flupenthixol (Fluanxol), fluphenazine (Modecate), haloperidol (Haldol), loxapine (Loxapac), perphenazine (Trilafon), pimozide (Orap), trifluoperazine (Stelazine), thiothixene (Navane) and zuclopenthixol (Clopixol).
Side-effects of this group of medications vary depending on the drug and may include drowsiness, agitation, dry mouth, constipation, blurred vision, and emotional blunting, dizziness, stuffy nose, weight gain, and breast tenderness, liquid discharge from breasts, missed periods, muscle stiffness or spasms.
2.2.1    Side-effects of typical antipsychotics
The extrapyramidal system (EPS) - the EPS is not a side-effect of antipsychotics, but needs to be mentioned before certain side effects. The EPS is a motor system composed of dopamine (DA) and acetylcholine (Ach) neurons which enjoy a reciprocal relationship. In some individuals when DA receptors are blocked, the balance in the system is disrupted, leading to side-effects.
Acute neurological side-effects (acute EPS effects) occur secondary to D2 receptor blockade in the EPS. These can appear on the first day of treatment and can take various forms of involuntary muscle spasm, particularly involving of the jaw, tongue, neck and eyes. A dramatic form is oculogyric crisis – in which the neck arches back and the eyes roll upward. A potentially dangerous form is laryngospasm – an early warning sign may be the patient’s voice becoming higher pitched. (Komossa et al, 2009).
Balance has been disturbed resulting in muscle spasm, and can be restored by acute treatment with oral or intramuscular injection of an anti-Ach – such as benztropine (2 mg). The response is immediate and pleasing.
Medium-term neurological side-effects are also due to D2 blockade in the EPS. Akathisia usually occurs within the first few day of treatment and involves either a mental and/or motor restlessness. Mental restlessness presents as increasing distress and agitation. Motor restlessness usually affects the lower limbs, with shifting from one foot to the other while standing and constant crossing and uncrossing of the legs while sitting. This is a difficult condition to manage. Useful steps include lowering the dose of the antipsychotic (if possible), adding diazepam or propranolol, or adding an anticholinergic (none of these agents is dramatically effective).
Parkinsonism usually occurs some days or weeks after the commencement of treatment. There is a mask-like face, rigidity of limbs, bradykinesia, and loss of upper limb-swing while walking. Tremor and festinating gait are less common. The best management is reduction in dose of the antipsychotic (if possible) and the addition of an anticholinergic agent. (Komossa et al, 2009).
Chronic neurological side-effects (late EPS effects) usually occur after months or years of continuous D2 blockade. Tardive dyskinesia (TD) manifests as continuous choreoathetoid movements of the mouth and tongue, frequently with lip-smacking, and may also involve the head, neck and trunk. Late EPS effects may continue after cessation of the typical antipsychotic.
Neuroendocrine effects result from blockade of dopamine transmission in the infundibular tract. Prolactin levels rise, with most antipsychotic agents and extreme cases may cause galactorrhea, amenorrhoea and infertility. (Komossa et al, 2009).
Neuroleptic malignant syndrome (NMS) is probably due to disruption of dopaminergic function, but the mechanism is not understood. Untreated, the mortality rate is 20%, and immediate medical attention is mandatory. The symptoms include muscle rigidity, hyperthermia, autonomic instability and fluctuating consciousness. Renal failure secondary to rhabdomyolysis is a major complication and the cause of mortality.
Anticholinergic side-effects include dry mouth, difficulty with micturition, constipation, blurred vision and ejaculatory failure. Anticholinergic delirium is a toxic confusional state; it usually occurs in patients taking a range of drugs directed at different symptoms, and antipsychotics may play a role.
Histamine blockade may produce severe sedation.
Alpha adrenergic blockade may produce postural hypotension, cardiac arrhythmias and impotence.
Dermatological side-effects include skin rash and photosensitivity
Weight gain is common with most typical antipsychotics.
Examples of antipsychotic medications
The oral forms of these medications are now uncommonly used.
Haloperidol produces EPS side-effects at high doses, but the oral preparation continues to be used in small doses (e.g., 0.5-1.0 mg bd) for brief periods for disturbed behavior in delirium and elderly patients. The IMI preparation (e.g., 10 mg) has a place in the management of younger disturbed people who are a danger to self or others (see later).
Zuclopenthixol continues to be used in two IMI preparations. Zuclopenthixol acetate (50-150 mg) is useful in the control of acute psychosis and disturbance. The beneficial effects last about 3 days. Zuclopenthixol decanoate (200-400 mg, 2-4/52) continues to command a small place in the long-term maintenance of chronic psychotic disorders.
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