Amisulpride, Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone, Sertindole, Zotepine
Neuroleptic medications may be prescribed to individuals deemed to be having 'psychotic' experiences e.g. hearing voices others do not hear, seeing things others do not see, strongly holding beliefs others believe to be abnormal, developing paranoid ideas etc. The atypical neuroleptics (also known as second generation) differ from the typical neuroleptics in that they in the majority of individuals induce fewer extra-pyramidal side effects (see later for explanation of term) and have a reduced effect on a hormone called prolactin (again, see later for explanation of relevance).
They may be prescribed in the short term in order to quieten 'disturbed' individuals, to individuals given a diagnosis of Schizophrenia, individuals deemed to be manic, individuals who have 'psychotic' experiences whilst depressed, individuals with severe anxiety, individuals who have suffered brain damage or are in a state of toxic delirium.
Neuroleptic medications are also sometimes referred to as 'anti-psychotic' medications. However, we believe this term to be misleading implying that the drugs specifically affect 'psychotic' symptoms, but this is not the case. Some individuals who have psychotic experiences find the drugs of no benefit to them, for others the side or adverse effects of the drugs strongly outweigh any beneficial effects the drugs may be having. But some individuals do find these medications useful.
The theory behind why individuals develop 'psychotic' symptoms is based upon the idea that there are elevated levels of dopamine in the brain. Dopamine is a neurotransmitter, a molecule that passes messages between neurons. For example, when a nerve impulse arrives at a dopaminergic neuron (also known as a pre-synaptic neuron), dopamine is released from the cell and diffuses through a space between two neurons, called the synaptic cleft. Dopamine then binds to specific dopamine receptors on a different neuron (post-synaptic neuron) producing a specific signal, impulse or effect. Dopamine is then released from its receptors and 're-absorbed' into the pre-synaptic neuron, or degraded by enzymes in the synaptic cleft.
The neuroleptics block dopamine receptors thereby inhibiting the ability of dopamine to attach to these receptors and generate signals. However, unlike the typical neuroleptics, the atypicals merely transiently block the receptors therefore allowing some dopamine to bind to the receptors and generate signals. The atypical neuroleptics are also able to block serotonin receptors located on dopaminergic neurons. When serotonin binds to these receptors it inhibits dopamine release. However as these receptors are blocked by atypical neuroleptics, the dopamine secretion is increased. The transient rather than permanent blocking of dopamine receptors and the blocking of serotonin receptors and subsequent increases in dopamine, it is for these reasons that the atypicals are thought to produce fewer adverse effects than the typical neuroleptics. However, the atypical drugs differ in their 'stickyess' when binding to dopamine receptors and also in the ratio of which dopamine ad serotonin receptors are affected. This may result in some atypicals producing higher levels of specific adverse effects than others. The atypicals may also bind to other receptor types, producing further adverse effects (see side effects of atypicals section).
The body will always try to maintain itself in a state of optimal conditions for cell functioning. Therefore if a drug is introduced that blocks a specific signal or function the body will try to compensate for this. So, if an atypical neuroleptic blocks dopamine receptors, the cell on which the receptors are located will sense that it is not receiving as many signals from the dopamine receptors as it used to. In the long term, the cell will respond by producing more receptors, in an attempt to get the level of dopamine receptor signalling it is used to. As well as producing increased numbers of dopamine receptors, the sensitivity of the dopamine receptors is increased. If an individual then decided to abruptly discontinue taking the atypical neuroleptic, the dopamine receptors would no longer be blocked and fully exposed. So should anything potentially exciting or stimulating happen, dopamine would be released and bind to the increased numbers of extra sensitive receptors, leading to increased dopamine transmission, over and above what would have occured before the atypicals were introduced. In this scenario, some individuals develop 'psychotic' symptoms, due to over flooding of dopamine receptors, which may be interpreted as a 'relapse'.
The development of psychotic symptoms when there is excess dopamine transmission (as may occur in abrupt withdrawal) may lead some individuals to believe that increased dopamine signalling may have been responsible for the psychotic experiences an individual initially had when the drugs were first prescribed. However, individuals who had no psychiatric history have been given a course of neuroleptic treatment, and when the neuroleptics were abruptly withdrawn some of these individuals developed 'psychotic' symptoms.
The doses listed below are the maximum safe amounts an individual theoretically could be prescribed daily. However, the usual 'therapeutic' doses will vary depending on the individual and the prescriber.
Neurons that secrete dopamine are primarily located in three discreet regions of the brain; substantia nigra, ventral tegmental area and the hypothalamus and pituitary. It is theorised that there is excess dopamine secreted from the neurons in the ventral tegmental area which send signals from the midbrain to the cortex and limbic regions of the brain. However, the atypicals do not specifically target the dopaminergic neurons in the ventral tegmental area, they affect all dopaminergic neurons. On top of that, many of the atypicals do not just interact with dopamine receptors, as previously stated they block certain types of serotonin receptors. They also interfere with other receptor subtypes found on neurons including; adrenergic, histaminergic and muscurinic receptors, all of which when interfered with can produce adverse effects to the individual taking the atypical.
To describe the side or adverse effects, it is easier to do it by looking at the brain regions in which dopamine receptors are found and look at the adverse effects created which are due to drug induced changes in these regions. The adverse efffects that may occur through the neuroleptics interactions with other neurotrasmitter/receptor systems will then be described followed by the drug specific side effects that are most commoly reported.
Parkinsonism: The neurons found in the /substantia nigra/ are involved in the initiation of muscular planning, and muscle co-ordination (e.g. walking). The major neurotransmitter co-ordinating the neurons in this region is dopamine. Therefore when neuroleptics block dopamine receptors/signalling, this can result in problems with co-ordination and movement. Individuals may develop a tremor, most commonly of the hand, stiffness and lack of or slowing of movement, difficulty initiating movement (e.g. rising from a chair). If the facial muscles are affected, individuals may appear expressionless, blank, may drool and there may be a slowing of or delay in speech. Abnormal movements tend to affect the hands and arms but the legs may also be affected. The respiratory muscles may also be involved, they can become disco-ordinated in their contractions which may result in breathlessness or wheezing. This can occur persistently or episodically (e.g. only at night). These effects can be reversed upon withdrawal of or a reduction of the neuroleptic.
Akathisia: This is a state of highly unpleasant physical and psychological restlessness. Many individuals may find it difficult to sit still and feel like they literally want to jump out of their skin. However, to an outsider observing there may be no noticeable discomfort. Individuals may feel extreme mental turmoil, feel strange 'unlike themselves', paniciky or experience strange or unusual impulses. As neuroleptics are supposed to reduce irritability and impulsivity an individuals expression of these experiences may not be taken seriously, however, these are definite side effects of neuroleptics and should be taken seriously.
Dystonia: Dystonia basically refers to when a muscle has gone into spasm. Virtually any muscle can be affected but the most commonly affected include the muscles of the mouth, eyes and jaw. When the mouth or larynx are affected individuals may find speaking, eating or drinking difficult, there may also be changes in the tone of the voice. When the eyes are affected the eyeballs may appear to roll up into the head so that only the whites of the eyes can be seen. These spasms can be reversed by neuroleptic discontinuation or with the institution of an anti-cholinergic drug (e.g Procyclidine). The jaw can become locked or clench abnormally for periods of time which can lead to dental problems. Muscle spasms can be very painful, and may be misdiagnosed as pain syndromes in the affected muscle regions.
Tardive dyskinesia: This term refers to a delayed (hence tardive) onset of abnormal movements of the face and mouth, but can also affect the muscles of the trunk and limbs and usually occurs after months or years of taking neuroleptics. Unlike other adverse effects of neuroleptics affecting the muscles, tardive dyskinesias may last for several months or years after the neuroleptic has been discontinued and anti-cholinergic drugs do not appear effective in reversing these effects. However, there is evidence suggesting that clozapine and quetiapine may be beneficial in supressing the dyskinesia. Involuntary movements of muscles of the mouth and tongue may look like lip smacking movements, protrusion of the tongue, grimacing and chewing movements. An association has been noticed between dose of neuroleptic and increased risk of developing tardive dyskinesia, however it has developed in individuals exposed to lower doses of neuroleptics for short periods of time.
Demotivation: Dopamine also has important roles in neuronal signalling in the regions of the brain thought to be responsible for motivation and the gaining of rewards. When the neuroleptics block dopamine receptors and hence reduce dopamine signalling in these areas, individuals may feel de-motivated or experience a state of 'in-difference'. Indifference has been refered to as a 'who cares' type of feeling, there is no real desire to do anything. This can be misinterpreted by mental health workers as the development of 'negative symptoms' in individuals who have been given diagnoses of Schizophrenia. Individuals also report feeling emotionally blunted, unable to feel anger, joy, contentment. This may affect individuals abilities to form relationships, search for employment, engage in social activities. It can be difficult to distiguish indifference and apathy from depressive demotivation or just life itself. Some individuals who develop these experiences can often be prescribed anti-depressants in an attempt to lift an individual, however, if the neuroleptics are the cause, anti-depressants will not necessarily help.
Dopamine also has important roles in neuronal signalling between the hypothalamus and pituitary gland. In the pituitary gland dopamine binds to dopamine receptors, which causes a decrease in the amount of prolactin released into the bloodstream. When neuroleptics block dopamine receptors in the pituitary, there is no longer any inhibitory factors controlling prolactin secretion, therefore relative prolactin secretion is increased. Prolactin functions in the body to increase breast size and milk production in mothers who have recently given birth. However, in individuals taking neuroleptics (except clozapine and quetiapine) raised prolactin secretion can lead to enlargement of the breasts (in both sexes) and an increase in milk production and secretion from the breasts. Raised prolactin levels may also interfere with a females menstrual cycles, causing irregular periods or stopping periods altogether (amenorrhoea).
There are other adverse effects of taking atypical neuroleptics which appear to be unrelated to the dopamine receptor blocking properties of the drugs and may be due to interactions between the drugs and other recepetor systems in the body. These will be discussed below.
Weight gain: Individuals taking olanzapine and clozapine have been shown to gain more weight than individuals taking other atypical neuroleptics, but weight gain is seen with all the atypical neuroleptics. The reasons why individuals commonly gain weight whilst taking neuroleptics is uncertain but it may be due in part to the ability of atypicals to block serotonin 2 receptors. Individuals may also be less active whilst taking atypicals due to sedation or demotivation (or boredom in the inpatient setting!) and there may be no compensatory reduction in appetite. There may be a drug induced reduction in metabolic rate however, this has not been proven. Individuals may also experience thirst when taking neuroleptics, and so to compensate drink more, if high calorie beverages are consumed this can also lead to weight gain. In some cases individuals have gained as much as 5 stones or more in weight and can affect an individuals self-confidence and physical health. Attempts to lose weight through dietting alone may prove difficult if atypicals are the cause of weight gain and individuals may become very frustrated and blame themselves. Some atypicals particularly olanzapine and clozapine can cause elevations in the levels of lipids (fats) in the blood and put individuals at risk of developing cardiovascular disease (strokes, heart disease etc.).
Diabetes: Some atypicals especially olazapine and clozapine have been associated with the development of diabetes. This may be related to the excessive weight gain these two drugs predispose individuals to as obesity can lead to the development of type 2 diabetes. However, use of these atypicals can also cause elevated levels of sugar in the blood which can lead to a state of 'insulin resistance'. Insulin resistance is a state where the bodies tissues do not respond to insulin in the way they should. Usually insulin is released when the levels of sugar in the blood is higher than it needs to be, insulin causes tissues (muscles, liver etc.) to absorb sugars from the blood and store them for times when energy is needed (e.g. exercise). When tissues become resistant to insulin, the sugar is not removed from the blood and if the blood sugar is at high levels for long periods of time, this can damage the blood vessels and predispose individuals to developing problems with their kidneys, heart, eyes and the peripheral nerves (in the feet and legs) can become damaged and sensation may be diminished in the affected nerve regions.
Sedation: Some atypicals as well as blocking dopamine and serotonin receptors also block histamine receptors. The resultant effects of this is that individuals may feel sedated whilst taking atypicals. This can be advantageous as it may help individuals get to sleep. However, there have been mixed reports about the quality of sleep. Some individuals have felt that they have 'slept more soundly' after discontinuing the drugs. The sedated feeling produced may also affect an individuals ability to concentrate at skilled tasks, (e.g. driving).
Effects of blocking cholinergic receptors: Dry mouth, constipation, stomach upsets, blurred vision may all develop in individuals taking atypicals which also block cholinergic receptors. These effects have been reported amongst all of the atypicals.
Effects of blocking sympathetic receptors: Atypicals which affect the sympathetic nervous system can cause individuals to feel sedated, develop low blood pressure (which may lead individuals to feel faint or faint when standing up suddenly from sitting), may affect a mans ability to sustain an erection. Individuals may also develop a full feeling in the bladder or develop an inability to pass urine.
Sexual side effects: These have been reported in upto 50% of individuals taking neuroleptics and include, in males, an inability to sustain erections, delay in or inability to ejaculate, involutary and sustained erections, involuntary ejaculations. Decreased libido or sex drive can affect both sexes and may be due to an general demotivation. Females have reported an inability to orgasm.
Neuroleptic Malignant Syndrome: A syndrome characterised by individuals developing muscular rigidity, decreased conscious level, hyperthermia and it can be fatal if not treated quickly. The syndrome tends to develop shortly after an individual starts taking neuroleptics or with rapid increases in neuroleptic doses or if an individual is taking many medications and has an infection or other physical problem. If symptoms of neuroleptic malignant syndrome develop, individuals should seek medical help immediately (e.g. A&E).
When discussing coming off psychiatric drugs the terms withdrawal and discontinuation will be used interchangeably. Although the term withdrawal is usually associated with coming off drugs to which an individual is addicted to, when an individual comes off neuroleptics they are not addicted to the drug, they do not consciously crave the drug. The effects an individual may experience when withdrawing/discontinuing/reducing a neuroleptic are not related to addiction but rather to the body struggling to adapt to the absence of a chemical it has become used to being present.