Like Neuroleptic Effects

Any drug that blocks D2, including every newer antipsychotic medication, will, in sufficient doses, produce a lobotomy-like effect. 

The very first report on the psychiatric use of chlorpromazine was published in France by Delay and Deniker (1952 translated in Jarvik, 1970). Their article described the actual state of the patient for a medical world that as yet had no familiarity with the drug  

Sitting or lying, the patient is motionless in his bed, often pale and with eyelids lowered. He remains silent most of the time. If he is questioned, he answers slowly and deliberately in a monotonous, indifferent voice he expresses himself in a few words and becomes silent. (Jarvik, 1970) 

They also described the patient as fairly appropriate and adaptable But 

Notice the nonspecific nature of these effects. Not only symptoms such as anxiety, but also desires and preferences, are aborted or buried beneath indifference or apathy. As Delay and Deniker put it, there is an apparent indifference or the slowing of responses to external stimuli and the diminution of initiative and anxiety (Jarvik, 1970). Once again, this is iatrogenic helplessness and denial with spellbinding effects. 

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Central Motor restlessness, progressing to maniacal agitation, psychic disturbances, disorientation, and hallucinations. Elderly subjects are more sensitive to such central effects, in this context, the diversity of drugs producing atropine-like side effects should be borne in mind e.g., tricyclic antidepressants, neuroleptics, antihistamines, antiarrhythmics, antiparkinsonian agents. 

Perhaps in response to growing professional and public criticism, psychiatrists have become much more reluctant to publish criticism of any treatments or to mention their brain-disabling effects. Nowadays the neuroleptic drugs are always described as having a specific antipsychotic effect, rather than a numbing, lobotomy-like deactivation effect. In the words of my research assistant, Ian Goddard, This remarkable difference between historic and contemporary commentary on the effects of neuroleptics clearly reveals the existence of an all-pervasive denial that has consumed the profession in modern times (2007, unpublished). 

I-Methyl-4-[3(5)-pyrazolyl]quinolinium iodides (688) also failed to depress blood sugar levels significantly (69JMC1124). Neuroleptic-like effects of some /3-aminoketones (689) containing a pyrazole nucleus have been described in the literature (B-80MI40406). The... 

Neuroleptic-like malignant syndrome is a serious but very rare adverse effect of some drugs, of e.g., neuroleptics, some anaesthetics and apparently tolca-pone. Symptoms include hyperthermia, muscle deterioration, even dissolution. 

Figure 17.5 Possible scheme for the initiation of depolarisation block of DA neurons. In (a) the excitatory effect of glutamate released on to the DA neuron from the afferent input is counteracted by the inhibitory effect of DA, presumed to be released from dendrites, acting on D2 autoreceptors. In the absence of such inhibition due to the presence of a typical neuroleptic (b) the neuron will fire more frequently and eventually become depolarised. At5q)ical neuroleptics, like clozapine, will be less likely to produce the depolarisation of A9 neurons because they are generally weaker D2 antagonists and so will reduce the DA inhibition much less allowing it to counteract the excitatory input. Additionally some of them have antimuscarinic activity and will block the excitatory effect of ACh released from intrinsic neurons (see Fig. 17.7)...

The mechanism by which 5-HT2 antagonism could ameliorate schizophrenic symptoms and what effect 5-HT has on mesolimbic and mesocortical pathways through A10 neurons is even less certain. It is more likely that 5-HT s action occurs postsynaptically in the limbic system or PFC. The probability that neuroleptics benefit from a particular balance of DA and 5-HT2A antagonism is developed later. 

Many of the neuroleptics are a-adrenoceptor antagonists. Some, like chlorpromazine, block d postsynaptic receptors while clozapine (and risperidone) are as potent at 2 as D2 receptors. There is no evidence that either of these actions could influence striatal or mesolimbic function but NA is considered important for function of the prefrontal cortex and any increase in its release, achieved by blocking a2-mediated autoinhibition, might contribute to a reduction in negative symptoms and provide a further plus for clozapine (see Nutt et al. 1997). Centrally, however, most a2-receptors are found postsynaptically and their function, and the effect of blocking them, is uncertain. 

Refractory cases respond to clozapine. If D2 antagonism is considered necessary, or at least desirable, for counteracting positive symptoms it is surprising that a relatively weak D2 antagonist like clozapine should not only be so effective but also prove successful in patients who have not responded to other neuroleptics more potent at D2 receptors. 

The administration of low doses of PCP to rodents induces hyperactivity and stereotypy (Chen et al. 1959 ). The observation that neuroleptics such as chlorpromazine, haloperidol, and pimozide, and adrenolytics such as alpha-methyl paratyrosine antagonize these behavioral effects of PCP suggests that they are mediated by facilitation of central dopaminergic neurotransmission (Murray and Horita 1979). The actions of PCP on central dopaminergic neurotransmission may be similar to amphetamine. A dose of PCP (2.5 mg/kg) in rats, which has no effects when given alone, enhances the behavioral effects of 1 and 3 mg/kg of d-amphetamine (Balster and Chait 1978). PCP, like dopamine, has also been shown to suppress plasma prolactin (Bayorh et al. 1983). However, the firm establishment of an excl usive relationship between dopamine neuro-transmission and PCP effects is difficult because of the prominent interactions of this drug with other neurotransmitter systems. 

Areca may interact adversely with antipsychotic medications (Deahl 1989). Two cases have been reported of schizophrenic patients who were taking neuroleptics and developed severe extrapyramidal symptoms after areca chewing. Given the functional antagonism between dopamine and acetylcholine in the striatum, it is likely that arecoline amplified the dyskinetic effect of neuroleptic medications. 

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. Hi-antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, clemastine, dimethindene, mebhydroline pheniramine) as antiemetics (meclizine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhydramine, p. 222). Promethazine represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most Hi-antihistamines are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. Hj-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 

Haloperidol is less likely to cause hypotension than chlorpromazine, which has a-adrenoceptor antagonist effects. Both can cause cardiac arrhythmias if used in high dosage or in patients with pre-existing heart disease, or as an idiosyncratic reaction. There have been numerous reports of sudden and unexplained deaths, probably due to cardiac arrhythmia, in patients given chlorpromazine and other neuroleptics. The risk of serious arrhythmia is higher in the obese, and possibly in those of African ancestry. 

In the late 1980s, clozapine a chlorpromazine like compound with a multiplicity of effects was rediscovered and termed an atypical neuroleptic. It appears to be the only genuinely atypical agent - that is an agent with significant beneficial treatment effects in the absence of EPS (see Wahlbeck et ah, 1999). A second generation of antipsychotics have succeeded clozapine been marketed as being atypical. 

Because the tardive syndromes that develop in adults are often irreversible and have no satisfactory treatment, care must be taken to reduce the likelihood of their occurrence. Antipsychotic medication should be prescribed only when necessary and should be withheld periodically to assess the need for continued treatment and to unmask incipient dyskinesia. Thioridazine, a phenothiazine with a piperidine side chain, is an effective antipsychotic agent that seems less likely than most to cause extrapyramidal reactions, perhaps because it has little effect on dopamine receptors in the striatal system. Finally, antimuscarinic drugs should not be prescribed routinely in patients receiving neuroleptics, because the combination may increase the likelihood of dyskinesia. 

The Schedule I designation of marijuana has been disputed over the past 15 or more years. Some physicians would like to see it as a Schedule II drug so that it could be used therapeutically in the treatment of the nausea, vomiting and anxiety caused by cancer chemotherapy and as an antiglaucoma agent (lowers intraocular pressure). It should be noted that the neuroleptic prochlorperazine is an effective antinausea drug which can be used without producing the psychoactive effects of marijuana. 

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