As a medical information specialist I am confronted with a variety of questions related to the trending therapeutic areas out there: immunoncology, cardiovascular, central nervous system, virology, orphan diseases, immunology, and so on and so forth. Every day I learn something new, from medical nomenclature to the mode of action of a certain drug, a wide range of topics pass through my eyes and I savour the opportunity to be well informed. Often, I myself, try to understand certain disease area aspects that are not so well explicit to the public or still remain a huge question mark for most of the healthcare professionals, clinicians and researchers out there.
Recently, I have asked myself 'Why is there a “delayed onset” of antipsychotic action when changing between products?' as this is a recurrent situation to which I was never offered a clear response. Why is it so typical of treatments with antipsychotics that the patients deriving from product A to product B will quite often experience an adaptation phase? I can immediately relate to, for example, some research work I did back in the days when I graduated and my final year research project covered Cushing's syndrome. The case study I prepared did partially look through the desensitisation experienced by the patient's organism after a certain period of exposure to the very same drug. Different active substances would perform differently in terms of the body responses to the drug (pharmacokinetics) and the effects of such drugs in the different human sub-systems (pharmacodynamics). But when you consider the same basic active agents however in different products, it's very unlikely (if not almost impossible) that the aggregating/stabilising salt where these molecules 'sit' would impact that much on the efficacy of the product.
I decided to investigate a bit further, and here's what I found on the delayed onset of antipsychotic action, especially when changing between products?
Effect timings
Apparently, when considering the findings of the review article by Agid et al (2006) [1] there isn't a delayed onset, and actually the antipsychotic effect is within the first day, however the strongest more 'visible' antipsychotic effects are produced in the first two weeks after administration. Still according to this review, the most improvement is obtained in the very first month of treatment against any other period of treatment or follow up.
Even though it does not immediately respond to the question, as there is no switch between products in the previous paragraph, it already offers some nice pointers to understanding this issue. Could all this be a myth? Let's continue investigating.
A myth or a theory?
Psychotherapy is full of acquired myths as it is the norm for any therapeutic area with considerable difficulty in scientifically measuring improvement. But according to [1] it was in the 70s when this idea appeared stating that the onset of antipsychotic action is delayed in about 2 to 3 weeks. This led to investigations on what would be the underlying causes prompting such delay; and some authors arrived to a possible theory known as 'The Depolarisation Block Theory'. As per the authors two studies suggest that the explanation for a delayed onset of action is based on preclinical studies (on paralysed anaesthetised mice) involving recordings of dopamine neuron firing proposing that the effect on dopaminergic neurons in the brain after repeated administration of an antidopaminergic drug (commonly known as antipsychotic) is the inactivation of firing that usually occurs only after ~3 weeks of continuous treatment with said drug - ergo, a delay onset. Consequently, clinicians and investigators thought that this reported delay explained the delay in the therapeutic effect of the administered drugs [2] [3] [4].
The fact is that this theory was so strongly believed as factual that researchers started looking for biomarkers to actually support it. If found, no one would dare question its prevalence and thus the theory would be validated into something more clinically and scientifically accepted. The idea of its consubstantiation was to basically grow the theory into a postulate, to then grow it into an axiom.
After many different attempts this theory was 'officially' refuted as so well discussed by Agid et al (2003) [5]. The authors quite well mention that for understanding the mechanism of action of antipsychotics it is crucial to have a clear understanding of the time course over which effects take place. [5] put to test the delayed-onset hypothesis by subjecting it to a meta-analytic study, meaning by subjecting 'a large amount of data from a multitude of studies' to a statistical combinatorial arrangement that in the end informs on whether effects in different studies are equal or vary to the next one. And sometimes, it is even possible to obtain from a meta-analysis study, the underlying reason why effects were different/same. Clever, isn't it? One got to love this STATS geniuses!
So by scrutinising 42 published studies, 7450 patients 119 independent treatment response and time curves, the investigators recognised that actually an 'early onset effect' was present even beating the timeline of the estimated effect of the placebo treatment!!! In conclusion, the analysis fully rejects the 'delayed onset' theory, reinforces the idea that effects initiates at first week and grows in strength over the proceeding weeks, and that the most 'readable/visible' signs of effect are observed two weeks after treatment has initiated [5].
Big names of the neuroscience field throughout the middle of the 20th century helped propagate this idea of 'delayed onset' of antipsychotics. This helped propagate yet another theory that resulted as the possible physiological explanation, the aforementioned 'depolarisation block hypothesis'. But because the precise time course of improvement observed after administration of antipsychotics in a patient-treatment has never been solidly scientifically established, this hypothesis cannot be assumed as having enough scientific backing to support its reliability.
As extremely well presented and discussed in [5], the crucial detail in this debate is to accept and differentiate 'delayed onset' from 'delayed realisation of full improvement' as suggested by the authors. OK, many people can say - 'Well, but the idea is to know when you feel better; it doesn't really matter if it's working or not in the body if in fact one can't feel the physical effects and improve'.
I give' em that. Makes perfect sense!!! ... But then, that is what happens in all medical areas, with specific differences concerning the class of pharmaceuticals used> Nonetheless, all pharmaceuticals will take their time to act upon the subject. What really makes an incredible difference in all of this debate is, in my opinion, four very important things:
1) The level of affliction - a patient who is feeling quite poorly will urge the healthcare professionals for an immediate effect of the administered treatment (drug or drugs) on the physical system; if compliance, quality of drug or prescribed treatment as a whole is not adequate, it is possible that the patient will turn on the drugs' supposed 'delayed onset' as the one factor undermining improvement to his/her health. Add to that a multitude of disease experts making noise about the same and there you go, you have built your much wanted axiom. But one can never forget that wrongly or incompletely postulated ideas are not scientific validations, and ... a headache is a headache, a psychosis is a psychosis.
2) The seriousness of the disease - The more complex a disease the harder it is for a single pharmaceutical to respond to improvement expectancy, especially when there is concomitant medication involved. That and to an extent, considering their different biochemical natures, will affect the perceiving of efficacy of the drug under scrutiny.
3) The drug's mode of action - drugs are not all acting the same way or via the same pathways. Physiological resistances are present as they would normally be in a hyper-dynamic responsive organism as the human body is. Where the effects might take different times to be 'concretely felt' by the patient, some drugs will operate differently or through different mechanisms even when the overall goal is the same. This will immediately impact on how rapidly their effects are observed, not only concerning its pharmacodynamics, but actual also in the sense of improvement felt by the patient.
[1] Agid, O., Seaman, P., Kapur, S. (2006). "The “delayed onset” of antipsychotic action — an idea whose time has come and gone". J Psychiatry Neurosci, 31(2), pp. 93–100.
The fact is that this theory was so strongly believed as factual that researchers started looking for biomarkers to actually support it. If found, no one would dare question its prevalence and thus the theory would be validated into something more clinically and scientifically accepted. The idea of its consubstantiation was to basically grow the theory into a postulate, to then grow it into an axiom.
After many different attempts this theory was 'officially' refuted as so well discussed by Agid et al (2003) [5]. The authors quite well mention that for understanding the mechanism of action of antipsychotics it is crucial to have a clear understanding of the time course over which effects take place. [5] put to test the delayed-onset hypothesis by subjecting it to a meta-analytic study, meaning by subjecting 'a large amount of data from a multitude of studies' to a statistical combinatorial arrangement that in the end informs on whether effects in different studies are equal or vary to the next one. And sometimes, it is even possible to obtain from a meta-analysis study, the underlying reason why effects were different/same. Clever, isn't it? One got to love this STATS geniuses!
So by scrutinising 42 published studies, 7450 patients 119 independent treatment response and time curves, the investigators recognised that actually an 'early onset effect' was present even beating the timeline of the estimated effect of the placebo treatment!!! In conclusion, the analysis fully rejects the 'delayed onset' theory, reinforces the idea that effects initiates at first week and grows in strength over the proceeding weeks, and that the most 'readable/visible' signs of effect are observed two weeks after treatment has initiated [5].
Big names of the neuroscience field throughout the middle of the 20th century helped propagate this idea of 'delayed onset' of antipsychotics. This helped propagate yet another theory that resulted as the possible physiological explanation, the aforementioned 'depolarisation block hypothesis'. But because the precise time course of improvement observed after administration of antipsychotics in a patient-treatment has never been solidly scientifically established, this hypothesis cannot be assumed as having enough scientific backing to support its reliability.
As extremely well presented and discussed in [5], the crucial detail in this debate is to accept and differentiate 'delayed onset' from 'delayed realisation of full improvement' as suggested by the authors. OK, many people can say - 'Well, but the idea is to know when you feel better; it doesn't really matter if it's working or not in the body if in fact one can't feel the physical effects and improve'.
I give' em that. Makes perfect sense!!! ... But then, that is what happens in all medical areas, with specific differences concerning the class of pharmaceuticals used> Nonetheless, all pharmaceuticals will take their time to act upon the subject. What really makes an incredible difference in all of this debate is, in my opinion, four very important things:
1) The level of affliction - a patient who is feeling quite poorly will urge the healthcare professionals for an immediate effect of the administered treatment (drug or drugs) on the physical system; if compliance, quality of drug or prescribed treatment as a whole is not adequate, it is possible that the patient will turn on the drugs' supposed 'delayed onset' as the one factor undermining improvement to his/her health. Add to that a multitude of disease experts making noise about the same and there you go, you have built your much wanted axiom. But one can never forget that wrongly or incompletely postulated ideas are not scientific validations, and ... a headache is a headache, a psychosis is a psychosis.
2) The seriousness of the disease - The more complex a disease the harder it is for a single pharmaceutical to respond to improvement expectancy, especially when there is concomitant medication involved. That and to an extent, considering their different biochemical natures, will affect the perceiving of efficacy of the drug under scrutiny.
3) The drug's mode of action - drugs are not all acting the same way or via the same pathways. Physiological resistances are present as they would normally be in a hyper-dynamic responsive organism as the human body is. Where the effects might take different times to be 'concretely felt' by the patient, some drugs will operate differently or through different mechanisms even when the overall goal is the same. This will immediately impact on how rapidly their effects are observed, not only concerning its pharmacodynamics, but actual also in the sense of improvement felt by the patient.
[1] Agid, O., Seaman, P., Kapur, S. (2006). "The “delayed onset” of antipsychotic action — an idea whose time has come and gone". J Psychiatry Neurosci, 31(2), pp. 93–100.
[2] Bunney, B S., Grace, A. A. (1978). "Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity". Life Sci., 23(16), pp. 1715-27.
[3] Grace, A. A., Bunney, B. S. (1986). "Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recording". J Pharmacol Exp Ther, 38(3), pp. 1092-100.
[4] Bunney, B. S., (1984). "Antipsychotic drug effects on the electrical activity of dopaminergic neurons". Trends in Neurosciences, 7(6), pp. 212-215.
[5] Agid, O, Shitij, K., Tamara, A. et al (2003). "Delayed-Onset Hypothesis of Antipsychotic Action: A Hypothesis Tested and Rejected". Arch Gen Psychiatry. 60(12), pp.1228-1235.
Post image by Laurynas Mereckas on Unsplash.
[3] Grace, A. A., Bunney, B. S. (1986). "Induction of depolarization block in midbrain dopamine neurons by repeated administration of haloperidol: analysis using in vivo intracellular recording". J Pharmacol Exp Ther, 38(3), pp. 1092-100.
[4] Bunney, B. S., (1984). "Antipsychotic drug effects on the electrical activity of dopaminergic neurons". Trends in Neurosciences, 7(6), pp. 212-215.
[5] Agid, O, Shitij, K., Tamara, A. et al (2003). "Delayed-Onset Hypothesis of Antipsychotic Action: A Hypothesis Tested and Rejected". Arch Gen Psychiatry. 60(12), pp.1228-1235.
Post image by Laurynas Mereckas on Unsplash.
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