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Clinicians can now select psychotropic agents from a wide choice
The discovery of neuroleptic and antidepressant drugs about 50 years ago marked a breakthrough in pharmacotherapeutics, which has revolutionised the therapy of many neuropsychiatric conditions. The efficacy of the early and then standard agents in alleviating depressive and psychotic symptoms and preventing their reoccurrence has been established in numerous trials, but other factors limit their utility. These include the facts that not all patients respond to treatment, and that they tend to often have an unacceptable incidence of side effects, many of which are neurological in nature—such as parkinsonism, dystonia, tardive dyskinesia, and seizures.
In an effort to match improved therapeutic efficiency with a better side effect profile, various new antidepressant and antipsychotic drugs have recently been developed. These are becoming widely used and their introduction may have important consequences for neurological practice.
According to the dopamine hypothesis for schizophrenia, limbic D2 receptor blockade is essential for a drug to have antipsychotic activity.1 Classic neuroleptic drugs, such as haloperidol, antagonise dopamine D2 receptors and their clinical efficacy correlates with inhibitory activity at these receptor subtypes. Haloperidol leads to parkinsonism in 15%-45% of treated schizophrenic patients.2
The development of clozapine with properties differing from traditional neuroleptic agents has heralded the era of “atypical” antipsychotic drugs which are claimed to have improved tolerability and effectiveness compared with conventional neuroleptic drugs. The effectiveness of clozapine in treating patients with schizophrenia refractory to other medications,3 coupled with a low incidence of extrapyramidal side effects, has been attributed to a unique receptor profile and marked a major advance in psychopharmacotherapy. However, therapy with clozapine is limited by its potential for serious adverse effects, in particular the induction of agranulocytosis in 1%–2% of patients and it is therefore considered a second line therapy. Patients treated with clozapine initially need weekly blood count screening, which is reduced to fortnightly after 18 weeks and then to monthly after 1 year of satisfactory blood results. All patients on clozapine have to be registered with the Clozaril Patient Monitoring Service.4 Other disadvantages of clozapine include its propensity to cause worsening confusion due to anticholinergic properties,5 and its potential to induce seizures.6 Seizures are seen with clozapine in up to 5% of patients with doses of 600 mg or more, but even on lower doses EEG changes may be noted. Generalised tonic-clonic and myoclonic seizures are the most frequent reported.
The new generation of antipsychotic drugs includes those that have a similar receptor profile as clozapine, such as olanzapine and quetiapine, and others, such as risperidone.
The term “atypical” relates to their low propensity to cause extrapyramidal side effects, and they have minimal effects on serum prolactin concentrations.7 The mechanism of this “atypicality” seems to relate to different receptor profiles—that is, broader receptor profiles or more selective dopamine receptor binding. Several mechanisms have been proposed.
Some atypical antipsychotic drugs occupy lower levels of D2 receptors (for example, 20%–50% for clozapine) than the classic antipsychotic drugs, which occupy between 80% and 90%.8 This effect is dose dependent and it has been proposed that it may be partly due to rapid displacement of these agents from the receptors by endogenous dopamine—that is, they are more loosely bound.9 The D2 receptor occupancy of olanzapine and risperidone is similar to traditional neuroleptic drugs at clinically used doses.
Newer antipsychotic agents generally have a lower affinity for striatal D2 receptors and some preferentially bind to limbic rather than striatal D2 receptors (for example, clozapine, amisulpiride).10,11 A possible explanation for this phenomenon would be that higher output of endogenous dopamine in the striatum displaces more D2 bound drug, compared with low output in the limbic cortex.12 Of all the newer drugs, clozapine is the only one that seems not to bind to the core of the nucleus accumbens.
Other relevant mechanisms might include a high affinity for muscarinic M1 receptors of some agents (for example, clozapine, olanzapine), that make them potent anticholinergic drugs. It has been argued that the simultaneous blockade of D2 and M1 receptors by these drugs may be much more effective in preventing parkinsonism than non-simultaneous blockade.9
Several atypical antipsychotic drugs also have a higher affinity for cortical serotonin (5-HT) receptors rather than striatal D2 receptors. The blockade of 5-HT receptors could explain the lack of parkinsonian side effects, as neuroleptic induced catalepsy can be reduced by serotonin antagonists such as mianserin or cyproheptadine or by lesions of serotonin nuclei. Reduced serotonin moderates the reduction in dopaminergic function, resulting from blockade of D2 receptors.13 It seems, however, that an at least 10-fold greater affinity for 5-HT than for D2 receptors is required to achieve this effect (as with clozapine or risperidone).9
A strong affinity to the dopamine D4 receptor has been proposed to be relevant in the atypical action of some new antipsychotic drugs, in particular clozapine. The therapeutic dose of clozapine correlates well with its dissociation constant at D4, and clozapine has a higher affinity for D4 rather than D2. The D4 receptor belongs to the D2 receptor family and it has been suggested that it may be a relevant receptor for mediating antipsychotic action.14 D4 receptors seem to be restricted to the limbic region, which could account for the reduced likelihood of clozapine to produce extrapyramidal side effects.15
Many mixed atypical compounds act on various other receptors—for example, histamine, sigma, or adrenergic receptors. In addition they influence GABA and neuropeptides including neurotensin, metencephalin, and cholecystokinin. Even though several hypotheses for a potentially important role of these actions have been proposed, the relevance in terms of therapeutic and adverse effects of treatment is not known.
Despite their common features, each of the atypical antipsychotic drugs has a different relative affinity for the various receptors, which accounts for their individual properties. Table 1 summarises the receptor profiles of haloperidol and various atypical antipsychotic agents.
Table 2 shows results of animal studies, which have measured the potential of different antipsychotic drugs to generate catalepsy and their effect on conditioned avoidance, which is sensitive for predicting ratios for activities against extrapyramidal side effects.16
Clinical trials concerning the rate of occurrence of drug induced movement disorders of different new antipsychotic agents have been difficult to interpret and compare, because often patients have been on conventional antipsychotic drugs until shortly before entering a trial. Clozapine has been most extensively studied and several reports indicate that it improves or halts progression of tardive dyskinesia, chronic akathisia, and drug induced parkinsonism.17 There have been no reports of cases of tardive dyskinesia in patients who have only taken clozapine, but no other antipsychotic drug.
Reports on the use of risperidone for patients with tardive dyskinesia are unclear, some suggesting induction and others suppression. Parkinsonism and akathisia have been reported to occur after risperidone18 and it seems to cause more extrapyramidal side effects than clozapine. The pharmacological profile of risperidone differs from clozapine, in that risperidone has a much higher affinity for D2 receptors and less anticholinergic properties.
Olanzapine has a similar pharmacological profile to clozapine; however, it has a slightly higher affinity to D2 and 5-HT receptors. The potential of olanzapine to cause extrapyramidal side effects is probably intermediate between clozapine and risperidone.19 Quetiapine, which has low D2 and also low 5-HT affinity, causes few, if any extrapyramidal side effects.20
Amisulpiride, which is a recently licensed sulpiride analogue, differs from other agents in that it exhibits selective affinity for D2 and D3 receptors and is devoid of affinity for other dopamine receptor subtypes, serotinergic or cholinergic receptors.11 The incidence of extrapyramidal side effects is dose dependent but lower compared with conventional antipsychotic drugs.2 Data on comparison with other newer agents are limited.
Because of their lesser potential to produce parkinsonism, atypical neuroleptic drugs have not only gained growing importance in the therapy of schizophrenia, but have also taken on a central role in the management of dopaminergic psychosis in extrapyramidal disorders such as Parkinson's disease or related conditions such as Lewy body dementia. Psychotic symptoms occur as a complication of drug therapy in about one fifth of patients with Parkinson's disease21 and commonly in Lewy body dementia. Although it may be possible in some patients to reduce antiparkinsonian therapy, this usually makes parkinsonism worse and may not be well tolerated. In this situation the use of atypical neuroleptic drugs is indicated.
The benefits and limitations of different atypical neuroleptic drugs in dopaminergic psychosis correspond to what would be expected from data of extrapyramidal symptoms in non-parkinsonian patients. Clozapine, which seems to have least extrapyramidal side effects in non-parkinsonian patients, has been most extensively studied for treatment of psychosis in Parkinson's disease. All published trials have been positive, suggesting good antipsychotic activity without worsening of parkinsonism. Clozapine seems to ameliorate psychosis in Parkinson's disease at much lower dosages than those required for schizophrenia.22,23 It has been suggested that clozapine may also have a beneficial effect on other behavioural symptoms of Parkinson's disease—for example, sleep disturbance, anxiety, and depression. In addition there have been reports of a beneficial effect of clozapine on parkinsonian tremor.24
Reports on the use of risperidone in treatment of dopaminergic psychosis have been slightly conflicting. Even though some trials show a beneficial effect on relieving psychotic symptoms, this has often been associated with a worsening of extrapyramidal symptoms or confusion.25 Similar to reports on non-parkinsonian patients, the effect of olanzapine in treating dopaminergic psychosis seems to lie between that of clozapine and risperidone. Whereas olanzapine seems to be effective in treating psychosis in parkinsonian patients, there have been some reports of worsening in motor function.26 Others, however, report no change of extrapyramidal symptoms.27 Data on the use of quetiapine in Parkinson's disease are limited, although several studies have shown improvement of psychosis without worsening of parkinsonism.28,29 There are only limited data available on the use of amisulpride in patients with extrapyramidal disorders.
The development of antidepressant drugs represents another important advance in psychopharmacology. The lifetime rates for major depression are between 3% and 19%30—a number that is probably higher for patients with neurological disease (for example, 25%-60% in patients with medically intractable epilepsy31). The original monoamine hypotheses suggested that depression is due to deficiency of one or another of three monoamines—namely serotonin, noradrenaline, and/or dopamine,32,33 and it has stood the test of time.
The almost unsurpassed efficacy of tricyclic antidepressant drugs (TCAs) is probably the result of their non-selective interaction with these monoaminergic neurotransmitters. However, their action on these and other transmitter systems (for example, cholinergic, histaminergic) produces a wide range of clinically relevant side effects, including cardiotoxicity and the occurrence of spontaneous seizures.34 This is relevant for any patient in whom the seizure threshold may be reduced. The exact neurotransmitter mechanisms underlying the proconvulsant effect are unclear.35
Early studies reported seizures in 3% to 4% of patients receiving TCAs,36 however many of these patients had predisposing factors. More recent studies reported rates of less than 1% for patients with no risk factors on therapeutic doses.37,38 The risk of seizures with TCAs is dose related and rises with increased plasma concentrations. Reviews of patients who have taken overdoses of TCAs report seizures in 3%–8%.39
Selective serotonin reuptake inhibitors (SSRIs), which were introduced in the late 1980s are chemically unrelated to tricyclics and tetracyclics and have a more selective effect on the reuptake of serotonin.40 The currently available preparations are citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. Citalopram is the most selective of the SSRIs, and it inhibits serotonin reuptake 3000 times more than noradrenaline (norepinephrine) reuptake and 22 000 times more than dopamine.41 The SSRIs are now the most widely prescribed antidepressant drugs. They are better tolerated, safer in overdose, and have a lower seizure risk compared with tricyclic drugs.42 However, there are some case reports of patients without predisposing factors, who have had seizures on therapeutic doses of SSRIs. Additional side effects include anxiety, sleep disturbance, sexual dysfunction, and gastrointestinal disturbance, which have been attributed to the action of increased serotonin concentrations on the 5-H-2 and 5-HT3 receptor subtypes.43 The SSRIs can also provoke extrapyramidal disorders including akathisia and dystonias.44
The latest generation of antidepressant drugs has been developed to derive their therapeutic benefits from tailormade action on specific receptors, as a basis for efficacy with better tolerability.45
Reboxetine is a highly selective noradrenaline reuptake inhibitor (NARI) with a low affinity to histamine, cholinergic, dopaminergic, and α1-adrenergic receptors. It has minimal interaction with the serotinergic system, which mediates side effects such as nausea or sexual dysfunction.46 Reboxetine has been shown to be as equally effective as imipramine and more effective than fluoxetine in treating severe depression,47 but is better tolerated compared with first generation antidepressant drugs.
Venlafaxine is a serotonin-noradrenaline reuptake inhibitor (SNRI), similar to first generation antidepressant drugs. It does not, however, interact with adrenergic, histaminergic, or cholinergic receptors, avoiding the side effects associated with activity on these receptor systems.48 Several studies have indicated at least equal and occasionally superior effectiveness of venlafaxine compared with other antidepressant drugs (imipramine, fluoxetine).49
Nefazodone is a serotonin antagonist/reuptake inhibitor (SARI), the most potent action of which is blockade of 5-HT2 postsynaptic receptors leading to a dual mechanism of action on the serotinergic system.50 Noradrenaline reuptake inhibition is only minimal and there is no interaction with histamine and cholinergic receptors. Nefazodone has a good side effect profile with low rates of sexual dysfunction; it lacks cardiotoxicity in overdose,51 and seems minimally proconvulsant.
Mirtazapine is a noradrenergic and specific serotinergic antidepressant (NaSSA). It increases noradrenergic and serotinergic transmission by blockade of central α2-auto and heteroreceptors. In addition it blocks 5-HT2 and 5-HT3 receptors so that the increased serotonin only stimulates 5-HT1 receptors.52 Mirtazepine is free of muscarinergic and α1-adrenergic side effects but acts on histamine receptors causing sedation and increased appetite.53 Mirtazapine seems safe in overdose and has a low potential to cause seizures.54 Several studies have shown equal or superior efficacy of mirtazapine compared with amitryptilline55 or trazodone.56
Table 3 summarises potential side effects associated with antidepressant action on different receptor systems. Table 4 summarises receptor profiles and epileptogenic potential of several antidepressant agents.
Another problem of using antidepressant drugs in patients with epilepsy relates to their ability to alter the action of the cytochrome P-450 system. Inhibition of individual isoenzymes may lead to increases in serum antiepileptic drug concentrations; notably, there are interactions between carbamazepine and fluvoxamine secondary to inhibition of CYP1A2.
The past decade has witnessed the evolution of a new generation of psychotropic drugs, and clinicians can now select agents from a wide array of choices. Many of these new drugs seem to have advantages over conventional drugs in terms of efficacy and neurological and other side effects. Early results of usage of these drugs in patients with neurological disease—for example, Parkinson's disease or epilepsy—are encouraging. However, further studies are needed to confirm these benefits.
Clinicians can now select psychotropic agents from a wide choice
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