Wednesday, 23 January 2013

What is the most gratuitously bad drug class - my vote goes to the 'atypical antipsychotics'


And within this class, to the egregious, multi-billion-dollar poison by the name of Olanzapine/ Zyprexa: my personal choice for the most worse-than-useless, evil-nasty-dishonest drug blockbuster of all time.

Any other candidates?


What follows is a shortened and edited version of:


The perversity of currently operative incentives in the drug development, research, marketing and clinical use can be illustrated by considering the example of the so-called ‘atypical’ neuroleptics, which have grown to become a standard part of modern psychiatric practice.

Atypicals represent a backward step in therapeutics, probably being no more effective, much more dangerous, and greatly more expensive than already-existing agents.


The traditional antipsychotics (aka. neuroleptics or major tranquillizers) are very powerful agents for controlling agitated and psychotic behaviour when compared with the drugs in use before their discovery. The pre-antipsychotic behavioural control agents had been mainly sedatives (e.g. antihistamines, barbiturates, bromides and paraldehyde).

However, the antipsychotics, such as chlorpromazine, haloperidol and fluphenazine decanoate – are now seen to be neurotoxic. They achieve their distinctively powerful behavioural control by making patients Parkinsonian in a dose–dependent fashion, with permanent neurological disease (tardive dyskinesia) as the long-term consequence of prolonged high dosages.

Furthermore, it is now apparent that antipsychotics induce dependence, so that withdrawal tends to provoke psychotic episodes, and patients who have never taken antipsychotics have a better prognosis than those who are maintained on them. Short-term benefits are achieved at the cost of long-term harm.

On top of this, antipsychotics are notoriously unpleasant. Indeed, patients hate them, since the emotional effects of Parkinson’s disease include emotional blunting, mental dullness and demotivation; and sometimes agitated feelings of akathisia (inner turmoil and physical restlessness). These are not ‘side effects’ of antipsychotics, on the contrary they are the core therapeutic action.

In a nutshell, antipsychotics work by causing the psychological symptoms of Parkinsonism.


So, traditional antipsychotics are exceptionally nasty drugs whose use should be minimized as a matter of policy, and for which safer and less unpleasant replacements should be sought. So much is probably uncontroversial, at least at a personal level among informed psychiatric scientists, although for structural, professional reasons this conviction is seldom clearly stated as such.

The main response to this state of affairs has been the displacement of traditional antipsychotics by a group of drugs self-styled as ‘atypical’ antipsychotics, such as clozapine, risperidone, quetiapine and olanzapine. Clozapine is not a 'neuroleptic', by classical definitions and the others of this class are much weaker neuroleptics than traditional drugs.

Because atypicals have less tendency to cause Parkinsonian symptoms and tardive dyskinesia than traditional agents, they are consequently less powerful at suppressing behaviour than traditional antipsychotics; but atypicals are powerful enough (it turns out) for most purposes.

It seems that in their clinical effect, atypicals are essentially the pre-chlorpromazine sedative antihistamines, re-invented and re-packaged for modern times.

Indeed, an old antihistamine such as cyproheptadine might well be counted as functionally an ‘atypical’ antipsychotic by today’s criteria i.e. it blocks serotonin 2 and cholinergic receptors, it is (probably, like many old antihistamines) only weakly anti-dopaminergic, it is powerfully sedative and it causes weight gain. Yet cyproheptadine, is an off-patent drug, and available cheaply over-the-counter.


But if most of the atypicals are only weakly neurotoxic they are instead ‘metabolic poisons’; having poorly-understood (this poor understanding itself being a damning indictment of the structural biases of contemporary psychiatric research) but clearly damaging effects on various aspects of energy metabolism.

Atypicals tend to cause physiological damage, such as glucose intolerance, diabetes and perhaps pancreatitis; gross weight gain and cardiac conduction problems.

Atypicals are also associated with significantly increased mortality, from a variety of causes.(Clozapine, notoriously, causes lethal blood dyscrasias, requiring continuous monitoring.)

These lethal side effects occur in the context of long-term prescription for psychiatric disorders which are often self-limiting and rarely fatal.


Perhaps the main useful lesson from the emergence of the ‘atypical’ (i.e. weak) antipsychotics is that psychiatrists did not actually need to make all of their agitated and psychotic patients Parkinsonian in order to suppress their behaviour.

Atypicals are highly sedative agents. Apparently, the kind of sedation provided by the ‘atypicals’ is sufficient for behavioural control in most instances.

This should not have been a surprise, since sedation was the standard method of controlling agitation and acute psychoses before the emergence of antipsychotics and in situations where antipsychotics were not available (e.g. in the Eastern Bloc and underdeveloped countries).


Indeed, the value of sedation should not be underestimated. Sedation is not merely a relatively safe way of controlling agitated behaviour; sedation also provides a potentially ‘curative’ benefit for psychotic patients with a causative element of delirium. Sleep has profoundly restorative qualities where sleep disturbance is severe and prolonged, as is the case for many psychotic patients. In sum, drugs which promote sleep likely have an ‘anti-psychotic’ effect, as well as making patients both feel and function better.


In terms of therapeutic value, it therefore seems likely that ‘atypicals’ are merely an unusually dangerous way of sedating patients. In therapeutic terms these drugs therefore represent a significant backward step.

Rationally, the atypicals should now be dropped and replaced with safer sedatives. Potential antipsychotic-substitutes which already exist would include benzodiazepines and sedative antihistamines, such as promethazine plus of course that original but unacknowledged atypical: cyproheptaidine.


So - if psychiatrists want a drug to make patients sleepy, then why not use cyproheptadine?

True, cyproheptadine may lack the advantages of vast expense, plus numerous and potentially lethal side effects of the modern 'atypicals' - but at least it shares the same basic mechanism, including the side effect of causing significant weight gain.

Since psychiatrists apparently want their patients to be both sleepy and fat - this would seem like the perfect answer.

Unless they really insist on using pricey poisons...



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