Antipsychotics classical

Waddington J and Casey D (2000). Comparative pharmacology of classical and novel (second-generation) antipsychotics. In PF Buckley and JL Waddington (eds), Schizophrenia and Mood Disorders (pp. 1-13). Butterworth-Heinemann, Oxford, UK. 

Atypical antipsychotics The second generation or so-called atypical antipsychotics have chemical, pharmacological, and clinical properties that are different from those of the classical antipsychotics/ neuroleptics. The most commonly used atypicals include clozapine, olanzapine, risperidone, and quetiapine. 

The efficacy of antipsychotics, with respect to dopamine receptors, results mostly from blockade of D -like receptors. Binding of the classical antipsychotics (e.g., bromocriptine and raclopride), however, is about two orders of magnitude stronger at D receptors compared with D receptors. The atypical antipsychotics,... 

It is common for both the depressive and manic phases to occur simultaneously in what is termed a mixed state or dysphoric mania. During these mixed episodes, the patient s mood is characterized by symptoms of both a depression and mania. Mixed episodes often have a poorer outcome than classic euphoric mania and, as a rule, respond better to certain anticonvulsants and atypical antipsychotic drugs than to lithium. As many as 50% of admissions to inpatient psychiatric facilities for the treatment of manic episodes appear to be for mixed manic states. The recognition... 

Lithium remains the treatment of choice for bipolar patients who experience classic euphoric episodes of mania. Current evidence suggests that those with mixed episodes or rapid cycling episodes respond preferably to anticonvulsants or atypical antipsychotic drugs. In addition to its use as a mood stabilizer, lithium is effective in converting unipolar antidepressant nonresponders to responders. Finally, lithium may also be an effective treatment for patients with clnster headaches. 

Consequently, the choice for a primary mood stabilizer in acute therapy now includes lithium, valproate, carbamazepine, and the atypical antipsychotics. Among these, lithium and valproate remain first-line agents. Valproate and lithium are probably equally effective in the treatment of classic euphoric mania, but valproate and, for that matter, carbamazepine do not appear to provide the same degree of protec-... 

Despite the widespread use of neuroleptics in maintenance treatment of bipolar disorder, there have not been any systematic studies of their suitability for this role. Through clinical experience it has been widely accepted that neuroleptics are useful adjunctive treatments to lithium and related drugs. Treatment refractory patients frequently respond to atypical antipsychotics such as clozapine or risperidone. Such adverse effects as EPS, cognitive dysfunction and weight gain frequently limit the long-term use of classical neuroleptics. For this reason, the atypical neuroleptics such as olanzapine and risperidone should now be considered as alternatives for maintenance treatment. 

There are no randomized, double-blind, controlled studies of hospitalized children and adolescents with acute mania. Two systematic, albeit open, studies of lithium in hospitalized, acutely manic adolescents had response rates of 67%-80% in classic manic adolescents, and 33%-40% in manic adolescents with prior ADHD (Strober et al., 1988 1998). In a discontinuation study in which manic adolescents stabilized on lithium were subsequently assigned double-blind to placebo or continuation treatment, the response rate was 53.5%, and the presence of prior ADHD made no difference in outcome (Kafantaris et al., 1998). However, the presence of psychosis decreased the likelihood of lithium response and antipsychotic medication was necessary for stabilization. Naturalistic discontinuation of lithium (because of noncompliance) after stabilization resulted in relapse rates of 90% vs. 37.5% for those remaining on lithium (Strober et al., 1990). A NIMH multisite study is currently examining this issue more systematically. 

Typical (classical) antipsychotics have been proposed for a wide range of disorders. In the context of EOS the following indications exist acute treatment, maintenance treatment, and relapse prevention of schizophrenic disorders acute treatment and maintenance treatment of schizoaffective disorders treatment of organic mental disorders with psychotic features and... 

Efficacy in maintenance treatment. Studies in adult schizophrenia concerning maintenance treatment have been especially interesting, because the majority of the patients were nonresponders to conventional antipsychotics. These studies demonstrate the superior efficacy of clozapine as maintenance treatment in therapy-refractory psychoses treated by classical antipsychotics. Beyond that, it could be demonstrated that clozapine was effective in reducing recurrence rates and duration of hospitalization. The superior efficacy of clozapine, although not its effects on recurrence or hospital stay, have also been demonstrated in adolescents suffering from chronic schizophrenia (Schulz et ah, 1996, 1997). 

In the Expert Consensus survey, the respondents endorsed risperidone, olanzapine, and quetiapine, in that order, followed by high-potency traditional antipsychotics, for managing self-injury. A placebo-controlled study comparing risperidone with a classical antipsychotic, such as haloperidol, could provide valuable data for this field. 

Ramaekers, J.G., Louwerens, J.W., Munjewerff, N.D., et al. Psychomotor, cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic. J. Clin. Psychopharmacol. 19, 209-221, 1999. 

The contraction of the central ring in the classical tricyclic agents to a dihydroanthra-cene is compatible with antidepressant activity though the resulting compounds at first sight more closely resemble the antipsychotic phenothiazines. Most of this small group of drugs owe their antidepressant activities to the inhibition of the reuptake of norepinephrine. 

The anion formed from the acetyl methyl group under reaction conditions then attacks one of the carbethoxy groups to form a cylohexanone to give (74-4) as the isolated product. The free acid obtained on hydrolysis of the ester decarboxylates to give the (3-diketone (74-5). In a classic apphcation of the Knorr pyrrole synthesis, the diketone is then allowed to react with 2-aminopentan-3-one. Since the latter is unstable, it is generated in situ by reduction of the nitrosation product from diethyl ketone. There is thus obtained piquindone (74-6) [76], a compound that displays antipsychotic activity. 

This group investigated patients presenting with acute schizophrenic symptoms who underwent a drug-free washout period, received lithium only initially, and then antipsychotics later (374). Lithium was ineffective for classic schizophrenia, but some patients who met criteria for schizophreniform disorder did respond to lithium. Whether schizophreniform illness is a variant of mood disorders (a reasonable hypothesis in view of their lithium response) or a separate entity that is lithium-sensitive is still unclear. It is known that these patients have family histories that include mood-disordered as well as schizophrenic relatives. In a small pilot study, physostigmine (a drug with possible antimanic but no antipsychotic properties) benefited schizophreniform patients who responded to lithium, but had no effect in those who did not (Carver DL, personal communication). 

As noted earlier, evidence indicates that atypical antipsychotics may also produce NMS ( 488). Several patients have developed NMS after treatment with clozapine, risperidone, or olanzapine. A few of these cases are classic NMS, with symptoms such as markedly elevated temperature and CPK levels. For each drug, approximately a dozen reported cases fulfill a reasonably stringent criteria for NMS, whereas the rest can be considered borderline. The number of NMS cases, however, appears low relative to use. In addition, some of the patients on clozapine who developed NMS were also receiving neuroleptics. There are cases of patients who had NMS on clozapine alone, however, and when rechallenged with clozapine experienced another NMS episode. Similarly, rechallenge with olanzapine- or risperidone-induced NMS has resulted in either questionable or definite reemergence of NMS. 

Controlled trials. Table 10-4 summarizes the results from four of the five well-controlled, albeit small, trials comparing lithium with an antipsychotic in classic manic patients. These studies presented their data in a way that allowed for inclusion in a meta-analysis. Each study was a well-controlled, double-blind design, finding lithium superior to an antipsychotic, and the meta-anaiysis of the combined studies demonstrated this difference to be highly statistically significant. 

Thus, although lithium therapy of sufficient duration may be the treatment of choice in classic milder presentations of mania, the adjunctive antipsychotics (especially the novel agents) may be preferable in conditions such as mania with psychosis and schizoaffective disorder, given their faster onset of effect and broader spectrum of activity (see the section Alternatiye Treat later in this chapter). 

Younger patients with schizophrenia may be less responsive to pharmacotherapy than adult patients ( 164, 165). Nonresponse to typical antipsychotics is as high as 40% to 50% in some reports. Thought disorder is the most drug-refractory of the classic psychotic symptoms in children and adolescents with schizophrenia. Thus, even when the more florid symptoms (e.g., hallucinations and delusions) abate following treatment with antipsychotics, these patients frequently continue to have substantial impairment in social functioning and scholastic performance. 

Similar examples abound in most fields of therapeutics. For example, the major tranquilizer chlor-promazine—the first drug found to have true antipsychotic properties—is a trivial modification of phenothiazine, which was known for decades and used as a de-wormer for livestock. The parent phenothiazine, and many of its structural modifications, have no antipsychotic activity at all it is only certain minor structural modifications that have the essential pharmacologic and therapeutic properties. (Chlorpromazine also happens to be a classic example of the serendipitous empirical-clinical method of discovery of a drug s unique therapeutic value, a method described below.)... 

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