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Abstract: The cornerstone in treatment of psychosis is antipsychotic drugs. Treatment options have increased over the years; newer
antipsychotic drugs with a proposed increased efficacy regarding negative and cognitive symptoms, but also a shift in side-effects
from neurological side-effects to metabolic side-effects have arisen as the new challenge. The basis of successful pharmacological
treatment is a fundamental understanding of the mechanisms of action, the desired effects and side-effects of antipsychotic drugs,
a good relationship with the patient and a thorough monitoring of the patient before and during treatment. The clinically relevant
aspects of antipsychotic drug treatment are reviewed; mechanism of antipsychotic drug action, clinical considerations in treatment,
switching antipsychotic drugs, polypharmacy, safety and patient preference.
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Amisulpride Aripiprazole Clozapine lloperidone Olanzapine Paliperidone Quetiapine Risperidone Sertindole Ziprasidone
Anticholinergic
Autonomic
EPS
Metabolic
Sedation
Prolactin
Receptor affinities Amisulpride Aripiprazole Clozapine lloperidone Olanzapine Paliperidone Quetiapine Risperidone Sertindole Ziprasidone
Dopamine (+++) (+++) (+) (+++) (++) (+++) (+) (+++) (+++) (++)
Muscarine (−) (−) (+++) (−) (+++) (−) (−) (−) (−) (−)
Adrenergic (−) (+) (+++) (+++) (++) (+++) (+++) (+++) (+++) (++)
Histaminergic (−) (−) (+++) (−) (+++) (+) (+++) (+) (−) (+)
T½ 12 hours 3–4 days 12 hours* 18 hours 30 hours 23 hours 7 hours 24 hours** 2–4 days 6–8 hours
Figure 1.
#
Adapted from the Danish Society of Clinical Psychopharmacology.
*Metabolism is biphasic with great interindividual variation (T½ = between 6–26 hours).
**Metabolism of the risperidone molecule has a T½ of 2–4 hours, but 9-hydroxy risperidone has T½ of 24 hours.
Clozapine has shown superiority in treatment-resistant lack of a daily routine for medication are common.30,64
patients, but this unique effect has not been found in The clinical assessment of adherence is difficult and
non-treatment-resistant patients.55 sometimes inaccurate, which can delay intervention.63
When using long-acting injectable antipsychotic drugs
Clinical recommendations adherence to treatment is known, and it is possible to
Antipsychotic drugs should ideally not be used until a intervene at an earlier stage, if the patient discontinues
proper physical examination has been performed, but treatment.64 The assortment of atypical long-acting
this might not be possible due to lack of cooperation injectable antipsychotic drugs is increasing, as drugs
from the patient. For the typical antipsychotics, the are in pipeline for marketing.
dose-response relationship seems to be an inverted
u-curve,56 suggesting excessive high dosages cause Time to onset of antipsychotic drug effect
side-effects such as sedation and EPS which often are It has been assumed that the antipsychotic effect
misinterpreted as negative symptoms. Similar is not occurred after several weeks of treatment.65 The
found with the atypical antipsychotics which might delay in treatment response was explained by the
be due to lesser tendency to cause EPS.57 Therefore, “depolarization block” theory; this theory arose
patients should always receive the lowest effective from animal studies that showed continued firing
dosage in order to get the optimum treatment of their from the dopamine neurons for three weeks after
symptoms with as few side-effects as possible. The the antipsychotic drug treatment was initiated.66,67
optimum dosage is differentiated with higher dosage Newer studies have shown an earlier effect,68–70 some
in the acute phase, and after stabilization an effort to with effect in the initial 24 hours.68 Other studies
reduce the dosage in the maintenance phase should have shown the greatest improvement in psychotic
be done. Today, atypical antipsychotic drugs are symptoms within the first two weeks compared
considered first line drugs and typical antipsychotic to every two week period afterwards.65 There is an
drugs should be reserved for patients not responding important distinction to be made between onset of
to atypical antipsychotic drugs due to an increased antipsychotic drug effect and full clinical effect of the
risk of developing TD.58 Even though, meta-analysis drug. There is no doubt that time to full clinical effect
support some difference in efficacy between the is delayed weeks to months, but the initial effect
atypical antipsychotic drugs, so far clinical response occurs earlier, and is distinguishable from a pure
has been highly individual and unpredictable59 sedative effect.65,68 Agitation in the acute phase of a
suggesting that choice of antipsychotic drugs should psychotic breakthrough is common, and treatment
be based on prior response to treatment, side-effect thereof by either antipsychotic drugs or tranquilizers
profile and the patient’s preference. In case of non- is important to minimize distress for the patient.71
or partial response more efficacious drugs, even
with a less tolerable metabolic profile, should be Switching Antipsychotic Drug
used. Clozapine should be reserved for patients not Treatment
responding to at least two antipsychotic drugs, or Switching antipsychotic drug treatment is common,
patients with schizophrenia having tardive dyskinesia e.g. shown in the CATIE trial, where all cause of
or severe suicidal ideations.60 In cases of persistent discontinuation was the primary outcome.8 The study
aggression in schizophrenia clozapine might be of was conducted under circumstances that resembled the
value due to a special antiaggressive effect.61 everyday clinic, and showed that 74% of participants
changed medication within 18 months.8
Depot formulations The most common reasons for switching
of antipsychotic drugs antipsychotic drug treatment are lack of efficacy or
Antipsychotic drug treatment is associated with a side-effects. Before switching a balance between the
lower risk of relapse compared to placebo treatment,62 anticipated effects and side-effects should always
but non-adherence to treatment is common when be thoroughly discussed with the patient,72 and the
treating patients with schizophrenia.63 Reasons for following should be considered: Method of switch,
non-adherence are many, but cognitive difficulties or pharmacokinetics of the antipsychotic drugs, risks
during change and adverse events in conjunction with treatment, if the patient isn’t informed of the effect.
switching treatment. Rebound insomnia usually resolves with time, but
Switching can be done either abruptly by can be minimized with a slow cross tapering, or
discontinuing the prior treatment and initiating the with a short period of treatment with tranquilizers,
new treatment at the same time; gradual switch by e.g. benzodiazepines.75
tapering off prior drug before initiating the new drug
or cross tapering by tapering off prior drug while Muscarinergic considerations
initiating the new drug. No evidence supports using There is risk of muscarinergic rebound when
any specific method of switching.73 switching from a drug with a high anticholinergic
effect to a drug with a lower or no antagonistic effect
Pharmacokinetic considerations on the muscarine receptor. The symptoms are nausea,
The half life of the drugs used in the switch is vomiting, diaphoresis and sometimes insomnia.75
important for timing of the switch. If switching from Slow tapering off the medication usually resolves
a drug with a long half life, e.g. depot formulation or the problem, but when an abrupt discontinuation is
aripiprazole, a slow down tapering is not necessary, necessary, e.g. agranulocytosis on clozapine treatment,
as the concentration decreases slowly. In contrast, substitution with anticholinergic drugs can minimize
e.g. quetiapine has a short half life, and therefore the rebound symptoms.74
new drug should be initiated and titrated up, before
lowering the dosage of quetiapine.74 Conclusions on switching
Below are the different important receptor systems Ideally before initiating a change in antipsychotic
discussed in relation to switch of antipsychotic drug drug treatment, the patient should be treated with
therapy. The general description of the receptor the initial antipsychotic drug in clinical relevant
systems can be found in the mechanism of action dosages and for sufficient time to see improvement.
paragraph. The patient should in general be informed about the
risks of adverse events and also the possible gains of
Dopaminergic considerations a switch, as to give the patient adequate information
Switch from a drug with a high affinity for the to make an informed decision regarding treatment,
dopaminergic receptor to a drug with a lower affinity but also to prepare the patient for possible adverse
encompasses a risk of rebound psychosis.75 This is events.
probably caused by dopamine hypersensitivity in The authors recommend the cross-titration method
the mesolimbic system where physiological levels because this method probably has the lowest risk of
of dopamine can cause psychosis because of lower relapse but the abrupt switch is necessary in cases of
dopaminergic antagonism. There is also a risk of severe adverse events. The physician should consider
rebound tardive dyskinesia that has been hidden by EPS the pharmacokinetics, receptor profiles of the drugs
on the previous drug, or caused by the hypersensitivity and reasons for changing medication before planning
of dopamine receptors.75 The occurrence of switch the switch. Atypical antipsychotic drugs receptor
emergent EPS can be seen when switching from a affinities and side-effect profiles can be seen in
drug with a low affinity for the dopamine receptor to Figure 1.
a drug with a higher affinity.
Polypharmacy and Concomitant
Histaminergic considerations Medication
The main concern when switching between drugs with Little is known about the combination of antipsychotic
different affinities for the histaminergic receptor is drugs, and the use of concomitant medication such as
sedation or lack hereof.75 Switching from a drug with benzodiazepines, antidepressant or anticonvulsants
high histaminergic receptor affinity to a drug with as described below. Antipsychotic polypharmacy
lower affinity, symptoms of histaminergic rebound can is defined as the concurrent use of two or more
occur, e.g. insomnia. The opposite switch can result antipsychotic drugs in a single patient.76,77 The use of
in massive sedation, and possibly lower adherence to antipsychotic polypharmacy is common even though
the evidence is sparse and mostly indicates increased known, e.g. addiction, cognitive problems, sedation
adverse effects, with no increased symptom control.76 and withdrawal symptoms.92,93
Polypharmacy is used in several other fields of Depression occurs in patients with schizophrenia,
medicine, e.g. treatment of hypertension, where and treatment depends on the phase of the psychotic
drugs usually have different pharmacological disease. The dose of antipsychotic drugs should be
mechanisms of action, e.g. beta blockers and thiazide increased when dealing with psychotic patients.
diuretics for hypertension. The assumed dopamine D2 Antidepressants should be reserved for patients with
blocking mechanism behind antipsychotic drug psychotic symptoms under control.94 One of the major
action is universal to all antipsychotic drugs, although problems with diagnosing depression in patients with
differences exist in receptor affinities for other schizophrenia is the existence of negative symptoms,
receptors as described earlier. The theoretical reason e.g. anhedonia, decreased range of expressed
for combining drugs to increase the antipsychotic emotion and lack of motivation, which can imitate
effect is therefore limited.77 Polypharmacy can be depression.95 The Calgary Depression Scale for
necessary in cases of, e.g. cross-titration and in the Schizophrenia can help to diagnose depression in
treatment of breakthrough psychosis.76 patients with schizophrenia differentiating depressive
If patients experiences antipsychotic drug induced from negative symptoms.95
hyperprolactinemia, and dose reduction or change
of medication is impossible, concomitant treatment Safety
with aripiprazole should be considered as this has Safety and side-effects
shown promise in reducing prolactin levels.78–80 The The side-effects of antipsychotic drugs are many but
mechanism behind this is probably a dopaminergic most side-effects can be linked to a single receptor
agonistic effect on the pituitary gland by aripiprazole, whereas the mechanisms of others are more complex
a partial dopamine agonist.78,80,81 or remain unknown. Antipsychotic drugs are often
Studies combining antipsychotic drugs with each used in patient populations where e.g. taking
other have shown limited effect on the psychotic overdose, substance misuse and increased burden of
symptoms in general, and in some cases even increased cardiovascular risk factors are common. This increases
the burden of side-effects.77 The augmentation of the demands of monitoring safety when treating with
antipsychotic drugs due to lack of efficacy should antipsychotic drugs. Patients with schizophrenia
generally not be used until treatment with clozapine have a reduced lifespan of approximately 15 years,
has been tried.13 even when controlling for suicide and accidental
In cases of partial response to clozapine, deaths, with cardiovascular disease as main cause of
augmentation of clozapine with anticonvulsants death. The exact contribution of medication remains
has shown some promise in improving psychotic unknown.96
symptoms,82,83 although the primary use of
anticonvulsants in combination with clozapine is to Cardiovascular and metabolic
lower risk of seizures during clozapine treatment.84 side-effects
The combination of clozapine and atypical From the very beginning of the antipsychotic era,
antipsychotic drugs has not shown great promise in antipsychotic drugs have been associated with
improving antipsychotic effects, although studies sudden death.97 Sudden death in otherwise healthy
have been conducted on e.g. risperidone, amisulpride, people is probably related to cardiac arrhythmia
and aripiprazole.85–90 A meta-analysis has shown a secondary to electrophysiological changes of ion
small but significant effect, but the clinical relevancy channels in the heart.98 Prolongation of the QT
of this is doubtful.91 The results of augmentation due interval to more than 500 ms has been associated with
to reduction of side-effects seem more promising. an increased risk of developing the potential fatal
The combination of antipsychotic drugs and cardiac arrhythmia Torsade de Pointes (TdP).99,100
benzodiazepines is used for treating anxiety and However, this mechanism only accounts for a minor
agitation even though evidence is sparse.92 The part of the increased mortality seen in patients
difficulties in benzodiazepine drug treatment are well with schizophrenia.101 The antipsychotic-induced
metabolic changes such as weight gain, increased risk few weeks and can be minimized by up-titrating the
of developing diabetes and dyslipidemia are far more dose slowly. Especially, elderly and pregnant women
important.102,103 Clozapine, olanzapine and quetiapine are vulnerable to α1 induced side-effects. Increases in
account for the antipsychotic drugs that cause the heart rate during treatment with antipsychotic drugs
worst metabolic changes but results from studies can also occur due to blocking of the cholinergic
in first-episode psychosis suggest that drugs prior receptors.110
considered as weight neutral such as ziprasidone are
associated with a moderate weight gain.104,105 Most Extrapyramidal side-effects
trials comparing antipsychotic drug effects on weight Extrapyramidal side-effects (EPS) occur due to
gain are limited by the fact that patients are receiving blocking of more than 75% of the dopamine receptors
antipsychotic drugs at baseline, i.e. patients switched in the striatum as described in the mechanism of
from a drug with high weight gain potentials to a drug action paragraph. Atypical antipsychotic drugs cause
with lower weight gain potentials would gain less less EPS than typical antipsychotic drugs but a dose-
weight or perhaps even lose weight on the new drug dependent relationship exist meaning that virtually
and vice versa. The mechanism of antipsychotic drug all antipsychotic drugs are capable of causing EPS,
induced diabetes is probably related to decreased even the atypical antipsychotic drugs.111 Clozapine
insulin sensitivity which is worsened further by and quetiapine have lower affinities for the dopamine
weight gain and central adiposity.106 For olanzapine receptors resulting in a rare association with EPS.112
and clozapine, a direct diabetogenic effect regardless Monitoring of EPS is important because EPS has
of weight gain has been established.102 Diabetic been associated with poor compliance, reduced
ketoacidosis can occur as an acute complication of quality of life, increased suicide rate and avoiding
antipsychotic treatment.107 Olanzapine and clozapine acute EPS symptoms decreases the risk of tardive
seem to have the highest prevalence but most cases are dyskinesia.113 EPS consists of the four following
reversible when discontinuing the offending drug.108 domains: Parkinsonism, dystonia, akathisia and
Glycosylated hemoglobin (HbA1c) is often elevated in dyskinesia.113
these patients,107 and a decreased HDL and increased Parkinsonism is manifested as bradykinesia,
triglycerides are associated with an increased risk tremor, rigidity and postural instability. Bradykinesia
of insulin resistance.38 It should be mentioned that can easily be misdiagnosed as the negative symptoms
estimating the contribution of the drug to metabolic of schizophrenia or major depression. Management
status might be difficult due to other factors such as a of Parkinsonism includes reducing the antipsychotic
sedentary lifestyle.109 drug dose or switching to a drug with lesser tendency
Dyslipidemia increases the risk of cardiovascular to cause EPS. Anticholinergic drugs are effective for
disease due to arteriosclerosis. Atypical antipsychotic treating antipsychotic drug induced Parkinsonism,
drugs affect both triglyceride and cholesterols.38 but due to side-effects e.g. dry mouth, cognitive
Results from the CATIE trials suggest that of the impairment, and tachycardia they should be reserved
atypical antipsychotic drugs clozapine, olanzapine and for emergent situations.43
quetiapine affect triglyceride and cholesterols the most.8 Dystonia occurs most frequently after intramuscular
Patients with antipsychotic-induced dyslipidemia injections of conventional antipsychotic drugs and
might benefit from life-style interventions or switch younger male patients seem to be at higher risk.114
to a more metabolic tolerable antipsychotic drug, but It can affect several muscle groups leading to
in many cases treatment with statins is necessary. oculogyric crisis (extraocular), blepharospasm (eyelid),
Several antipsychotic drugs function as antagonists buccolingual crisis (face, jaw, and tongue), opisthotonus
at the α1 noradrenergic receptors causing venous (paravertebrals), retrocollis, anterocollis, torticollis
vasodilatation and a drop in blood pressure. To maintain involving neck, tortipelvic crisis (trunk and pelvis),
the same cardiac output, an increase in the heart rate, or laryngeal-pharyngeal dystonia. Acute laryngeal
called reflex tachycardia, occurs.110 Drugs with potent dystonia is a potential fatal condition.115 Administration
α1 antagonism cause orthostatic hypotension but of intravenous anticholinergic drugs and subsequent
tolerance to this side-effect usually develops after a dose reduction of the offending antipsychotic drug
often resolves the problem. A rare variant of dystonia associated with seizures whereas risperidone seems
called tardive dystonia which has a poor outcome to be safer.121,122 The mechanism for antipsychotic
and no response to anticholinergic drugs can occur.113 drug induced seizures remains speculative, but
Botulinum toxin might help these patients.116 involvement of muscarine and histamine receptors
Akathisia is an inner feeling of restlessness has been suggested.120
often located in the lower limbs presented in the
clinic as an inability to sit or stand calmly. It can Hyperprolactinemia
be misdiagnosed as agitation with the risk of Secretion of prolactin from the pituitary gland is inhibited
worsening the situation by increasing the dose of the by dopamine, and due to the dopamine receptor blocking
offending antipsychotic drug to treat the agitation.117 properties of antipsychotic drugs hyperprolactinemia can
Treatment includes reducing the antipsychotic drug occur. The symptoms are amenorrhea, gynecomastia,
dose or switching to a drug with less tendency to galactorrhea, sexual dysfunction and osteoporosis.
cause akathisia. Anticholinergic drugs are seldom Symptoms of hyperprolactinemia should always be
effective in resolving akathisia, unless Parkinsonism investigated and a probable cause found.
is present, whereas propranolol or benzodiazepines Increased prolactin levels have been associated
often are more effective.113 with an increase in the risk of breast cancer.123 The
Dyskinesia is most common in its tardive forms lipid solubility of antipsychotic drugs is important
and consists of involuntary movements and a specific as high solubility facilitates easier diffusion over the
syndrome called buccolinguomasticatory (BLM) blood-brain barrier. Antipsychotic drugs with low
syndrome which is one of the most common types. lipid solubility are given in higher dosages to reach
Tardive dyskinesia usually occurs after several years clinical relevant intrathecal concentrations, and as the
of treatment with typical antipsychotic drugs and pituitary gland is located outside the blood-brain barrier
is often irreversible. The mechanism is not fully higher concentrations of dopaminergic antagonistic
understood but increased sensitivity at postsynaptic drugs results in higher risk for hyperprolactinemia.124
dopamine receptors after longstanding antipsychotic Especially risperidone and amisulpride are associated
drug blockade is probably involved.118 Dose reduction with symptomatic hyperprolactinemia due to their
or switching to an atypical antipsychotic drug with low lipid solubility and high dopamine affinity,125,126
less affinity for the dopamine receptors is first choice but paliperidone has also been implicated, but is not
when treating tardive dyskinesia.119 Increasing as extensively studied yet.127 Quetiapine and clozapine
antipsychotic drug dosage might inhibit tardive are not associated with hyperprolactinemia.124
dyskinesia due to Parkinsonism but worsen the long- Aripiprazole has due to the high affinity for
term prognosis. In contrast, switching to a drug with dopamine receptors and the partial dopamine agonist
less affinity for the dopamine receptors might cause mechanism the ability to reverse antipsychotic induced
a transient worsening of the tardive dyskinesia due hyperprolactinemia.78,128
to less Parkinsonism. Anticholinergic drug treatment
should be discontinued as this often worsens tardive Sedation
dyskinesia. If the tardive dyskinesia does not resolve, Several receptors e.g. muscarine M1, noradrenergic
treatment with clozapine and/or tetrabenazine can be α-1, serotonin 5-HT2A/C, GABAA and histamine are
initiated.119 involved in causing sedation.129 However, antipsychotic
The annual risk for developing tardive dyskinesia drug sedation is mainly due to an antagonistic effect on
is around 5% for the typical antipsychotic drugs and the histamine receptor.129 Antagonism at the dopamine
around 1% for the atypical antipsychotic drugs.58 receptors can elicit anhedonia and lack of motivation,
mostly due to lack of reward and drive, but clinically
Seizures it can be difficult to distinguish from sedation induced
Antipsychotic drugs lower the seizure threshold which by antihistamine effects.130 FDA gave a black box
should be taken into account in patients at high risk warning for parenteral olanzapine in combination
for seizures, e.g. alcohol withdrawal and epilepsy.120 with benzodiazepines due to deaths probably caused
Especially higher plasma levels of clozapine are by excessive sedation.131 Same precautions should
be taken during titration of clozapine due to its large inter-individual variation in plasma levels and
hypotensive and sedative properties, or other drugs because a therapeutic threshold at 350–420 µg/L
with similar receptor profiles.132 has been found. TDM in general has only a minor
role in dose adjustment of antipsychotic drugs,
Neuroleptic malignant syndrome because no concentration-response relationship has
All antipsychotic drugs are capable of inducing been found for most antipsychotic drugs.141
neuroleptic malignant syndrome (NMS) which is a
potential fatal complication. The syndrome consists Cognitive side-effects
of four symptoms: Hyperpyrexia, EPS, altered Cognitive deficits are seen in patients with schizophrenia
mental state and autonomic instability, but not all are before the onset of psychosis and initiation of
necessarily present.133 Especially for NMS involving treatment,142,143 and can be linked to functional outcome,
atypical antipsychotics, EPS is not always present.134 e.g. employment and compliance to treatment.30,144
Laboratory findings include elevated creatinine kinase, These deficits can be exacerbated or improved by
leucocytosis and arterial blood gas acidosis. The pharmacological interventions. Anticholinergic effect,
exact mechanism for NMS is unknown but dopamine either administered as an anticholinergic drug, e.g.
blockade is undoubtedly involved.135 In case of NMS biperiden, or as antagonistic effect on the muscarinergic
all antipsychotics drugs should be discontinued and receptors decreases cognitive function, especially
in more severe cases treatment with bromocriptine memory and attention.46
and dantrolene is indicated.135 Benzodiazepines can Sedation reduces the general arousal level, and a
be used for treatment of mild to moderate cases, decreased or increased level of arousal can probably
and in controlling agitation. ECT is also effective in impair cognitive functioning as suggested in the
treating NMS.135 Yerkes-Dodson law, which means that sedation,
e.g. histaminergic antagonism, can improve cognition
Serious clozapine related side-effect in hyperaroused patients and decrease cognitive
Clozapine is associated with blood dyscrasias; functioning in others.51
approximately 0.8% develops agranulocytosis and 3% Other concomitant treatments can influence cognitive
neutropenia which elucidate the need for hematological functioning, especially treatment with benzodiazepines.
monitoring.136 Most cases of agranulocytosis occur This has not yet been tested in patients with
during the first six months of treatment and after a year schizophrenia, but cognitive testing on patients with
the risk is similar to treatment with phenothiazines.136 other chronic psychiatric disorders has shown
Olanzapine and quetiapine have also been associated significant decreases in cognitive functioning compared
with neutropenia, but do not seem to cause to controls, and a significant improvement after
agranulocytosis.137,138 discontinuation.93,145,146
Besides the blood dyscrasias, clozapine is also Atypical antipsychotic drugs in comparison with
associated with myocarditis and tachycardia. typical antipsychotic drugs show a slight advantage
Myocarditis develops during the first months and in cognitive improvement in favor of the atypical
symptoms are: Fever, tachycardia, dyspnea and antipsychotic drugs, even though this finding is
chest pain. ECG might show ST-elevation, but the questioned by suboptimal study designs in studies of
best way to diagnose myocarditis is to do troponin typical versus atypical antipsychotic drug effects on
levels.139 Cardiomyopathy is a long-term side-effect cognitive functioning.147 This is further questioned by
which seldom occurs until after six months of findings indicating that the difference between atypical
treatment and common symptoms are: Peripheral and typical antipsychotic drugs is non-existing when
edema, tachycardia, exertional dyspnea and fatigue. treating with optimal dosages of both drugs.147,148
Cardiomyopathy is detected through ECG changes
and clinical symptoms, but should be confirmed by Metabolism of antipsychotic drugs
echocardiography.140 The most important metabolic pathway for most
Therapeutic drug monitoring (TDM) is antipsychotic drugs is the cytochrome P450 (CYP450)
recommended during clozapine treatment due to the system149 that metabolizes drugs before they can be
excreted through the kidneys, but other metabolic take up to several weeks before maximum effect
pathways like the aldehyde oxidases that is involved occurs, as it is caused by an increased production
in the metabolism of ziprasidone exist.149 of CYP450 enzymes. In contrast, inhibition occurs
The CYP450 system consists of over 50 different immediately and reaches maximum effect when the
enzymes that metabolize a large number of compounds inhibiting drug reaches steady state.149 As induction
which allows the body to function under different is caused by an increase in the CYP450 enzyme, the
conditions and adapt to new expositions.150 effect is also prolonged after the offending drug is
The CYP450 enzymes primarily responsible discontinued, until the CYP450 enzyme again has
for the metabolism of antipsychotic drugs are reached its habitual activity.149
CYP1A2, CYP3A4 and CYP2D6.149,151,152 Most Amisulpride and paliperidone are not metabolized
antipsychotic drugs are metabolized by several in the liver,149,152,153 but are excreted directly through
CYP450 enzymes,151 but an inhibition or induction the kidneys unchanged. This knowledge can be used
of the primary CYP450 enzyme can have clinical when treating patients with severe liver disease.152
implications for the individual patient depending on
the width of the therapeutic index of the involved Patient Preference
drugs, the existence of additional metabolic pathways, Treatment of patients with psychotic illness
patient’s sensitivity to desired and adverse effects should not only focus on ameliorating psychotic
and the strength of the inhibition or induction.149 symptoms as measured by scales, but a more
In Figure 2, an overview of the most important holistic approach including the patient’s subjective
substrates, inhibitors and inductors are depicted. experience with the treatment, e.g. desired effects,
Induction of the CYP enzymes is a process that can side-effects, cultural acceptance of treatment, and
Figure 2.
#
Adapted from the Danish Society of Clinical Psychopharmacology.
*Several substrates metabolized by the same enzyme can increase plasma levels, but only if substrates surpasses enzyme capacity. This interaction is
seldom of clinical importance.
**Particularly potent inhibitors, consider alternatives.
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