I have searched the national library of medicine but I could not find any papers about predicting both the therapeutic and adverse effects on the specific patient (individual) in front of us.

People work on/ have an extremely similar chemistry (all cells do that was the phenomenon that the theory of evolution explained) but it is not identical (absolutely) across individuals otherwise we should predict drugs would have absolutely the same effects on all individuals.

As drugs do have different effects across individuals the expectation of the effects should be different too. Because we now know that they have a similar but slightly non-homogeneous chemistry.

How can we earnestly predict the effects, both therapeutic and adverse, of psychotropic drugs on the specific patient in front of us?


Predicting individual side effects is generally not feasible in current clinical practice, although in the purview of "personalized medicine", mostly as a research goal/topic. For psychotropic medications, this is largely envisaged to work through pharmacogenomics:

In pharmacogenomics, genomic information is used to study individual responses to drugs. When a gene variant is associated with a particular drug response in a patient, there is the potential for making clinical decisions based on genetics by adjusting the dosage or choosing a different drug, for example. Scientists assess gene variants affecting an individual's drug response the same way they assess gene variants associated with diseases: by identifying genetic loci associated with known drug responses, and then testing individuals whose response is unknown. [...]

Scientists believe many idiosyncratic effects result from individual variation that is encoded in the genome. Thus, genetic variation in genes for drug-metabolizing enzymes, drug receptors, and drug transporters have been associated with individual variability in the efficacy and toxicity of drugs. Genetics also underlies hypersensitivity reactions in patients who are allergic to certain drugs, such as penicillin, wherein the body mounts a rapid, aggressive immune response that can cause not only a rash, but can also hinder breathing and cause edema to the point of cardiovascular collapse.

Predicting serious ADRs [adverse drug reactions] is a priority for pharmacogenomic research. For example, the enzyme CYP2D6, one of a class of drug-metabolizing enzymes found in the liver, breaks down and terminates the action of certain antidepressant, antiarrhythmic, and antipsychotic drugs. Molecular cloning and characterization studies of the gene that codes for this enzyme have described more than 70 variant alleles (Meyer, 2000). These alleles contain one or more point mutations, only some of which affect enzyme activity; however, some of these alleles involve gene deletions and duplications that can lead to increased enzyme activity. Individuals who are homozygous or heterozygous for the wild-type or normal activity enzymes (75%–85% of the population) are called extensive metabolizers; intermediate (10%–15%) or poor (5%–10%) metabolizers are carriers of two alleles that decrease enzyme activity (Ingelman-Sundberg, 1999); and ultrarapid metabolizers (1%–10%) are carriers of duplicated genes. The most common alleles can be detected by DNA chip microarrays, allowing most patients to be assigned to a particular phenotype group. [...]

With the completion of the Human Genome Project, anticipation was high that genetic information would radically improve medicine, that side effects would be more predictable, and that patients could be screened for likely drug responses. But thus far, progress has been much slower than what the initial excitement suggested.

A great deal of this delay relates to the fact that an individual's response to drugs is multifactorial, resulting from multiple gene and environmental interactions (Haga & Burke, 2004). Scientists also recognize that even as the knowledge base continues to expand, the clinical translation of that knowledge still requires empirical evidence, generated for a particular disease and drug combination, before treatment can be customized to a patient's genotype. Thus, much work remains to be done before personalized medicine can reach its fullest potential.

Last year the FDA has issued a warning against improper/premature use of pharmacogenomics to select antidepressants. An excerpt...

For example, the FDA is aware of genetic tests that claim results can be used to help physicians identify which antidepressant medication would have increased effectiveness or side effects compared to other antidepressant medications. However, the relationship between DNA variations and the effectiveness of antidepressant medication has never been established. The FDA is aware that health care providers may have made inappropriate changes to a patient's medication based on the results from genetic tests that claim to provide information on the personalized dosage or treatment regimens for some antidepressants. [...]

There are a limited number of cases for which at least some evidence does exist to support a correlation between a genetic variant and drug levels within the body, and this is described in the labeling of FDA cleared or approved genetic tests and FDA approved medications.

As noted in a review of last year there are now several guidelines trying to put together the available knowledge:

There are multiple guidelines in various stages of development during the past 5 years including those by the Clinical Pharmacogenetics Implementation Consortium (CPIC), a registered service mark of the US Department of Health and Human Services and other authoritative scientific consortia [(e.g., Dutch Pharmacogenetic Working Group (DPWG)] for cytochrome P450 and drug therapy including for psychiatry.

CPIC has a database page roughly ordered by the drug in question, e.g. "CYP2D6, CYP2C19 and Selective Serotonin Reuptake Inhibitors". The DPWG guidelines currently seem to be one large (book-sized) pdf document, not restricted to psychotropic drugs. Various papers, e.g. Lunenburg et al. describe how their methodology (and thus sometimes conclusions) differs from CPIC etc. The latter consortium also publishes journal papers on their individual drug guidelines, e.g. they have one on "Genotypes and Dosing of Tricyclic Antidepressants".

  • $\begingroup$ I would like to focus more on the therapeutic effects. Maybe I should have added Predict AND Explain the effects because I am afraid that without an explanation probably any prediction would come serendipitously. $\endgroup$ – George Ntoulos Jan 4 '20 at 0:27

How can we earnestly predict the effects, both therapeutic and adverse, of psychotropic drugs on the specific patient in front of us?

The basic answer is that you cannot necessarily predict accurately how any medication will affect any individual person.

Medications can in general, carry risks of side effects. The risk levels of each side effect will also be different. Anyone who is licensed to prescribe medications have access to enough literature to assess the level of risk based on risk factors known to the medical profession.

As an example, here in the UK, we have the British National Formulary (BNF), which provides guidance on prescribing in general, as well as guidance on prescribing for children and those who are pregnant etc.

Detailed information is also given as to the drug indications and dose, contra-indications, known side effects and risk factors among other things to consider.

An example side effects list etc. for Paroxetine (a Selective Serotonin Reputable Inhibitor) can be viewed at https://bnf.nice.org.uk/drug/paroxetine.html (NOTE: I have been advised that this may be restricted to UK website visitors only). An alternative example from the US is from drugs.com

  • $\begingroup$ The last link is indeed inaccessible from across the channel. Brexit galore! $\endgroup$ – AliceD Jan 3 '20 at 10:50
  • $\begingroup$ @AliceD - I could be wrong, but I don’t think that it is due to Brexit :-) I think it could be due to different licensed indications for each drug or something along those lines. Although saying that, we do have access to drugs.com outside the US $\endgroup$ – Chris Rogers Jan 3 '20 at 10:56
  • $\begingroup$ It does not need to be absolutely free of Statistical Errors. Type I or Type II. I just need a system, a methodology to scientifically predict rigorously, systematically, methodologically the effects of the drugs( most importantly the therapeutic effects). I am good with a moderate Type I error and a moderate Type II error what I am not okay with is prescribing drugs through serendipity. Statistics fail when a theoretical background is absent. $\endgroup$ – George Ntoulos Jan 4 '20 at 0:15

Therapeutic effects and adverse reactions of psychoneuro-pharmaceutical drugs are tested using the same gold standard as usd for more conventional drugs, namely in randomized controlled trials.

  • Phase I trials focus on side effects and dosages in a small group of healthy subjects.
  • Phase II testings assess efficacy and side effects in a medium-sized population of patients.
  • Phase III testing assesses efficacy, effectiveness and safety in large numbers of patients. The outcome will tell you whether the drug works, how well it works and what side effects are to be expected and how often they occur.

These data do not allow to predict effects and side effects in a specific patient; they only allow you to estimate the chances that a drug will work and what side effects can be expected based on population testing.

Because of the renewed interest in psychoactive compounds to treat depression and addiction, there is currently an increasing trend to conduct RCTs on compounds like psilocybin (Lewis, 2019).

- Lewis, Sci Am, January issue (2020)


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