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Manfred Ackenheil
Professor of Psychiatry and Pharmacology
Head of Department of Neurochemistry
Psychiatric Hospital
Ludwig-Maximilians-University Munich
Munich, Germany
E:[email protected]
Treatment of psychiatric patients is carried out according to the nosological categories that implicate affective depression and schizophrenia psychosis. These categories are based on clinical descriptions used for the modern classification systems ICD-10 and DSM4. They neglect the biochemical and physiological abnormalities involved in the pathogenesis of these disorders.
The pathophysiology of these disorders is heterogeneous and can have many different causes. No wonder that for any kind of psychiatric disorder a great number of nonresponders can be observed. Nonresponders may show individual pharmacokinetic and pharmacodynamic variability due to genetic heterogeneity on the level of the main neuron transmitter systems in the brain. In reality, many of the symptoms being treated occur transnosologically.
Treatment of symptoms and behavioural abnormalities that can be attributed to disturbances of the various transmitter systems is known as “functional pharmacology”. For example, reduced activity of the serotonergic system can be best treated with specific serotonin reuptake inhibitors (SSRIs). Reduced serotonergic activity is related to many symptoms and behavioural abnormalities (see HPE 2003;
Issue 8:53-5).(1)
Several psychiatric disorders can occur simultaneously – three different diagnoses in a single individual is not unusual. Patients commonly present with depression and anxiety, or schizophrenia and obsessive-compulsive disorder (OCD), or occasionally drug abuse. Comorbidity is more the rule than the exception.
Most patients are treated according to a trial-and-error basis. Even in so-called evidence-based medicine studies, based on multicentre trials with up to 1,000 patients, efficacy is usually statistically evaluated. In general, the response rate of such studies is slightly over 50%, which means that a great number of patients do not respond to treatment. The severity of the illness plays a major role – those with suicidality are excluded from placebo-controlled studies and are less likely to respond in clinical practice. In clinical practice many patients will require a more sophisticated treatment approach. Reasons for the nonresponse of such patients are:
- Heterogenity of the disorders being treated, with various physiopathologies being responsible
- Individual differences in metabolism and variations in receptors, transporters and enzymes. Genetic variations may alter a patient’s receptor structure, which can affect their affinity for drugs.
Pharmacokinetic aspects
Pharmacokinetics – the metabolism of medicines in the body – depends on the activity and genetic variations of the metabolising enzymes, the P450 cytochromes. The activity of these enzymes determines drug plasma levels in the blood and the spectrum of metabolites produced, which are responsible for the effects and side-effects of the drug. The characteristics of the different cytochromes in relation to drug effects are shown in Figure 1.(2) Different genetic forms (alleles) exist of all of these enzymes – cytochrome 2D6 occurs in 12 different variations that show different metabolising activities – slow metabolisers, extensive metabolisers and ultrarapid metabolisers result from such variations.
[[HPE09_fig1_55]]
Haloperidol is metabolised via CYP2D2, CYP1A2 and CYP3A4 to reduced haloperidol, piperidine metabolite and pyridinium metabolite HPP(+). The allele CYP2D6(*)4, which occurs in approximately 20% of Caucasians, determines a slow metabolism. In one study, patients with this allele showed higher plasma levels of haloperidol and reduced haloperidol. Reduced response to therapy and more extrapyramidal side-effects were observed. The neurotoxic HPP(+) could also be detected in the blood in higher levels. Patients who are heterozygous for the CYP2C19 2A allele also show less side-effects. Patients carrying the cytochrome 1A2(*)1F show a poor drug response with regard to negative symptoms measured with the PANSS scale.
Similar effects can be observed with other psychotropic drugs. Our own results show that, in patients given a similar dosage, up to 10-fold variations in plasma levels can be seen for clozapine and amisulpride (see Figure 2). Plasma levels that are too low or too high reduce the therapy response and can be the cause of many undesirable side-effects.
[[HPE09_fig2_56]]
Pharmacodynamic aspects
Pharmacological effects and side-effects vary according to genetic variations in the different receptors. The effects of both classical and atypical neuroleptics are mainly due to the blocking of dopaminergic receptors in the nigrostratial and mesolimbic dopamine system. Five different dopamine receptors, D1–D5, have been distinguished. D1 and D5 stimulate the adenylate cyclase enzyme, whereas D2, D3 and D4 inhibit adenylate cyclase. All antipsychotics inhibit the dopamine D2 receptor to a more or less marked degree, and this is most important for their antipsychotic effect. Clozapine has a greater affinity for the dopamine D4 receptor than haloperidol. The o-substituted benzamides – amisulpride and sulpiride – show a predominance for the dopamine D3 receptor. Other receptors of the serotonin, noradrenaline, histamine and muscarin systems are blocked as well.
This blockade contributes to the effects and the side-effects of the different antipsychotics. The blockade of the serotonin 5H2A receptor in particular reduces psychotic symptomatology and diminishes the occurrence of extrapyramidal side-effects.
Genetic variations in the different dopamine and other receptors play a role in therapy response. The dopamine D3 receptor exists in two polymorphisms. According to our unpublished results, as well as those of others, atypical antipsychotics show a better efficacy if one allele with a BAL1 polymorphism in exon 1 exists.(3) Classical antipsychotics like haloperidol are less effective in such cases. However, the response to treatment depends on more than one allele, and one single allele contributes only partially to variability in drug response. In a large investigation, Arranz et al showed that the serotonin 2A receptor, the serotonin 2C receptor, the histamine H2R receptor and the serotonin transporter 5HTT2PR also play a major role.(4) The combination of the different polymorphisms present permits a prediction of therapy success with 77% accuracy, holding promise for future management strategies. Other examples, such as the APOE4 allele in dementia, underline these results, and similar results are reported in antidepressant treatment. Variations of a subunit of the G-protein coupled receptor or the angiotensin-converting enzyme (ACE) contribute to the response to treatment with antidepressants.(5)
Future prospects
The future of psychopharmacological treatment will be oriented towards a more individualised therapy. If we start from symptomatology rather than from nosology, the heterogeneity of the disorder and its different pathophysiologies has to be considered more. Furthermore, variations in the effects of the drugs themselves, due to genetic variations on the level of pharmacokinetics and pharmacodynamics, will contribute to the success of new treatments.
New molecular biology techniques will allow the simultaneous genotyping of different candidate genes that are responsible for these pharmacokinetic and pharmacodynamic effects. Knowledge of the activity of the different metabolising enzymes will allow prediction of drug plasma levels. Beside the candidate genes that are known today, other genes will play an important role. Such unknown genes can be detected by pharmacogenomics: screening of the whole genome, or with proteomics screening for all the proteins that may be changed during therapy. These methodologies will pave the way to an individualised patient-centred therapy.
References
- van Praag HM. Make believes in psychiatry or the perils of progress. New York: Brunner Mazel; 1992.
- Brosen K. Drug metabolising enzmes and therapeutic drug monitoring in psychiatry. Ther Drug Monit 1996;18:393-6.
- Scharfetter J, Chaudhry HR, Hornik K, et al. Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 1999;10:17-20.
- Arranz MJ, Munro J, Birkett J, et al. Pharmacogenetic prediction of clozapine response. Lancet 2000;355:1615-6.
- Bondy B, Zill P, et al. Psychopharmacogenetics – a challenge for pharmacotherapy in psychiatry. World J Biol Psychiatry 2001;2:178-83.
