The atypical antipsychotic drugs: a new perspective in the treatment of major psychiatric disorders

Garonna Franco, Stifani Luigia *

presented at the Ukranian-Italian Meeting "Psychopharmacotherapy and Psychotherapy", Lviv, 9-11 October 1998

* Vicenza - Italy

Since the advent of neuroleptic drugs in the treatment of Schizophrenia, the pharmacological and clinical research has been focused on other chemical compounds different from the "typical", "classical", or "traditional" D2 blocking antipsychotics for an improved therapeutic profile, that means improved efficacy on all the spectrum of the symptomatology (both positive and negative symptoms) and decreased side effects ( extrapyramidal in particular).

The classical pathogenetic hypothesis of Schizophrenic Disorders is founded on the evidence that neuroleptic drugs exercise their therapeutic action as dopamine receptors antagonists.

In fact, typical dopamine agonists like amphetamines produce psychotic symptoms (delusions, allucinations).

Therefore, the antipsychotic efficacy is supposed be related with potency of D2 receptors blocking in mesolimbocortical and nigrostriatal dopamine systems.

Brain dopamine projections are organized into four major circuits: the nigrostriatal, mesolimbic, tuberoinfundibolar, and incertohypothalamic systems.

The nigrostriatal circuit is one of the most extensive dopamine systems in the brain. The deficits in motor function in individuals with Parkinson's disease are the consequences of the destruction of most of the dopaminergic neurons in this circuit. The presynaptic neurons of this system are located in area A9 (pars compacta of substantia nigra). The mesolimbic cortical dopamine system originates in area A 10 (ventral tegmental area). A9 and A 10 are involved in the mechanism of action of the antipsychotic medications.

The necessity of new antipsychotic drugs is related with several considerations: traditional D2 blocking drugs are not often so effective in all the psychotic symptomatology; neuroleptics produce important and persistent side effects as EPS, neuroendocrine disorders, and others which condition negatively individual’s social functioning and quality of life. Furthermore there is a theoretical consideration: we are not anymore so sure that the pathogenesis of Schizophrenia pass through the traditional dopaminergic system alterations. As a matter of fact, there are several pieces of evidence that other systems and pathways into the CNS are involved.

The utility of the serotoninergic system in the therapeutic approach to the Schizophrenic Disorders is confirmed by recent studies. Serotonin projections tonically inhibit mesolimbic and nigrostriatal dopaminergic activity, therefore the 5-HT receptors antagonism may protect the system from the dopamine depletion induced by neuroleptics, and increase the dopaminergic activity in cortex frontal areas. This pharmacological action protects from iatrogenic Parkinsonism, and improves cognitive and operational functioning.

According to present clinical and pharmacological advancements, we may point out that the complete dopaminergic blockade is not necessary for the antipsychotic activity.

Both positive and negative symptoms of Schizophrenia are basic for the onset and the development of the disease, predictors of the outcomes in cognitive and social impairment.

All these symptoms are the target of the pharmacological intervention, which must tend to attenuate the negative impact of the symptomatology on the quality of life.

The selectivity in receptors binding affinity characterizes Clozapine, the prototype of atypical antipsychotic agents, from Haloperidol. Clozapine has more affinity for D receptors in the Cortical Areas than Haloperidol which blocks D2 receptors in Nigrostriatal System. This specific mechanism of action makes Clozapine lack of extrapyramidal side effects, invariably produced by Haloperidol and other typical neuroleptics for their unselective D2 receptors blocking.

The receptors binding affinities of the atypical antipsychotic drugs is expressed in Ki, higher is the value lower is the affinity. Clozapine, among all of them, shows lower D2/5-HT2 ratio (Tab 1).

Comparing the different binding affinity of traditional and atypical antipsychotics, Haloperidol and Pimozide have major D2 affinity than Clozapine and Risperidone. Fluphenazine has less affinity than Haloperidol, and we know how higher are the EPS with Haloperidol and other high potency antipsychotic drugs of the same chemical class with respect of the aliphatic chain neuroleptic drugs.

Risperidone compared to typical and atypical antipsychotic drugs has a more favourable Serotonin receptors affinity. The clinical meaning of this biological data may consist in a more activating function, which is required in more inhibited and deficitary clinical presentations of Schizophrenic Disorder. Risperidone must be used with some caution in Schizoaffective Disorder because it may cause switching to manic phase. It is contraindicated in bipolar patiens, if it is not associated with Lithium or other mood stabilizers.

Haloperidol and Clozapine are different for Serotonin receptors binding affinity. Major difference concerns 5-HT2a, 5-HT3, 5-HT6. This last receptor site is exclusively localized in the CNS. Loxapine, which may be considered the most atypical among typical antipsychotic drugs, as well other traditional antipsychotic medications, displays a relatively high affinity for 5-HT6. Some Authors consider this receptor site interesting for the pathogenesis of Schizophrenia and the antipsychotic mechanism of action.

Clozapine, the prototype of the new antipsychotics for its particular receptors affinity profile, is compared with Haloperidol, the prototype of the traditional antipsychotics: Clozapine has more affinity for D1 than D2, and has more affinity for 5-HT1a, 5-HT1c, 5-HT2 and above all 5-HT3, in comparison with Haloperidol which has more affinity for D2 receptors than for Serotonine receptors.

Clozapine, Olanzapine and Quetiapine have similar chemical structures, different from Risperidone, Sertindole and Ziprasidone which are similar among themselves.

Clozapine (Novartis), Clozaril in USA, Leponex in Italy and Europe, was first reported to be an effective antipsychotic medication by Austrian and German clinicians in the mid-1960s.

In 1974, as Clozapine’s popularity was growing in Europe, eight patients in Finland died from Clozapine –associated agranulocytosis, and the routine use was discontinued in many parts of the world. This is the reason because Clozapine received the approval from U.S. FDA only in the fall of 1996.

Clozapine has great antipsychotic efficacy and lack of extrapyramidal side effects.

The occurrence of agranulocytosis is in 1 %- 2 % of treated patients, with reports of occasional fatalities. A careful laboratory monitoring is required to detect agranulocytosis and more serious neutropenia.

Clozapine reaches steady state in 1-6 hours, 97 % binds to serum proteins, is almost completely metabolized by the liver prior to execretion, its elimination half life is 4-12 hours, that means at least two administration a day are required.

Clozapine is considered the prototypical agent of the atypical antipsychotic medications, for its mechanism of action which makes it lack of extrapyramidal side effects, and is strongly indicated in patients with EPS from traditional neuroleptics and Tardive Diskinesia.

Its mechanism of action consistds in an icreased D1/D2 ratio, D3-D4 antagonism, 5-HT2a – 5-HT2c antagonism, anticholinergic and antiadrenergic properties, a mesolimbic D blockade specificity, relatively to a nigrostriatal D sparing.

The main side effects are: mielotoxicity, seizures, hypersalivation, hypothension, urinary incontinence, weight gain. The recommended dosage is 200-600 mg. b.i.d/t.i.d..

The official indications for use of Clozapine in U.S.A. and in Europe are:

"Treatment refractory" schizophrenic patients
Patients with severe EPS from neuroleptics
Tardive Diskinesia
Clozapine in the A.P.A. guidelines for the treatment of Schizophrenia is indicated as "gold standard" in pharmacotherapy of drug refractory patients with Schizophrenia.

Some clinical reports show other useful indications of Clozapine and atypical antipsychotics:

Schizoaffective and Bipolar Disorders, alone or in association with mood stabilizers
Severe neurologic diseases, like Parkinson’s and Huntington’s diseases, behavioural consequences of severe head injuries, dementias and mental retardations
Aggressive behaviours in Personality Disorders
The response to Clozapine in treatment resistant schizophrenics may be delayed beyond 6 - 12 months.

In these cases augmentation strategies may be required before changing Clozapine with another antipsychotic drug :

association with Lithium
association with SSRI to potentiate 5-HT activity (Fluoxetine, Fluvoxamine, Paroxetine) or with other antidepressants (Tricyclic, Mirtazepine) in order to ameliorate negative simptomatology.
association with high potency D2 blocking agents (Haloperidol, Sulpiride, Amisulpride).
Several studies suggest that Clozapine in monotherapy regimen or associated with other specific drugs (Lithium, Valproate, Antidepressants) is effective in Bipolar Disorders.
Risperidone (Janssen) was introduced in 1993 in the U.S.A. and also exists in Europe with the name of Risperdal.

Risperidone is extensively metabolized by epatic Cytocromes (CYP2D6) in an active form, 9-hydroxy-risperidone. This lenghtens the elimination half life, about 20 hours, and makes useful the monodosage once a day, with the advantage of a good patient compliance. The mean peak plasma concentration is reached in about 1 hour, steady state in 1-6 days.

Risperidone acts as an atypical antipsychotic compound. EPS may appear when the dosage is over 9 mg. daily. Its main mechanism of action consists in D2, 5-HT2a, alpha 1-alpha2 antagonism, lack of anticholinergic effect. The reported side effects are somnolence, fatigue, orthostatic dizziness, tachycardia, nausea, dyspepsia, diarrhea, weight gain, sexual disfunction, rhinitis.

The recommended dosage is 3-6 mg. u.d./b.i.d..

Sertindole was discovered and patented by Lundbeck Company (Denmark). It is introduced in Europe with the name Serdolect. It has not yet been approved by FDA for the U.S. market. The mean elimination half life is 3 days, is metabolized by CYP2D6 and CYP3A in dehidrosertindole and norsertindole, inactive metabolites.

Sertindole has the same biological properties of other new antipsychotycs.

The lenghtening of E.C.G. QT interval, observed in some cases, is the most relevant side effect that induces a certain caution in the first weeks of treatment. This effect is completely reversible with the interruption of the treatment. Sertindole is a potent 5-HT2a antagonist, moderate alpha 1 antagonist, weak D2 antagonist. It has a high selectivity of action in Ventral Tegmental Area (D activity suppression) than in Substantia Nigra Pars Compacta. Other side effects are decresaed ejaculatory volume and weight gain. The recommended dosage is 16-24 mg. u.i.d./b.i.d..

Quetiapine (Zeneca) is structurally related to Clozapine and Olanzapine. Seroquel has now become the trade name under which it is marketed in U.S. and Europe. Quetiapine has high affinity for 5-HT2a brain receptors, lower affinity for D2, D1 receptors, lower muscarinic, cholinerrgic, alpha 1 antagonism than classical neuroleptics. It ha very low incidence of EPS, no sustained elevation plasma prolactine, no anticholinergic side effects. The recommended dosage is 150-800 mg. t.i.d..

Ziprasidone (Pfizer) is the newest antipsychotic drug which is coming into the market in U.S.A. and Europe. A multicentric european trial is still in progress.

The interesting biochemical profile of this compound will make it available in several psychotic conditions, not only in Schizophrenia.

The property to inhibit both Na and 5-HT re-uptake makes Ziprasidone very useful to cure depression in severe psychotic patients.

Olanzapine (Lilly) is of particular note because it is structurally related to Clozapine, and has similar atypical antipsychotic properties, but it does'nt have the same bone marrow toxicity. Olanzapine blocks the NMDA receptor - mediated excitotoxicity induced by phencyclidine. This property is very interesting in light of the most recent theories about psychotic syndromes and glutamatergic neurotransmission.

Zyprexa is the trade name of Olanzapine in U.S. and in Europe. The plasma levels peak is reached in about 5 hours. The average elimination half life is 27 +/- 2 hours. The elimination half life increases with age. The drug is extensively metabolized by the liver.

Zyprexa, for its pharmacodiynamic and pharmacokinetic profile, clinical efficacy and safety may be considered, to date, one of the best treatment of Schizophrenia and other Psychotic Disorders.

The ideal antipsychotic medication should be:

Rapidly active on positive symptoms, and lack of marked sedative action.
Effective in the negative symptomatology, ensuring good performances in social and occupational life.
Well tolerated and safe in the long term treatment.
Effective in a broad spectrum of clinical conditions inside the psychotic framework.
What makes atypical an antipsychotic medication may be summarized in the following properties:

Selectivity of action in CNS areas (mesolimbic cortical area, frontal cortical area)
Favourable D/5-HT ratio in the receptors blockade mechanism
No extrapyramidal side effects, at least into the therapeutic dose range
Clinical effectiveness on positive and negative symptomatology
Tolerability and safety in the acute and long term treatments
The introduction of "atypical antipsichotic drugs" have generated a new era for the therapy of schizophrenic patients.

Newer atypical antipsychotic agents may further increase the understanding of the pathogenesis of Schizophrenia and expand treatment alternatives.


HIRSCH S.R., WEINBERGER D.R. Eds.: Schizophrenia. Blackwell Science Ltd. 1995.

SCHATZBERG A.F., NEMEROFF C.B. Eds: Textbook of Psychopharmacology. American Psychiatric Press 1998.

SHRIQUI C.L., NASRALLAH H.A. Eds.: Contemporary Issues in the Treatment of Schizophrenia. American Psychiatric Press, 1996.

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