The Future (or Lack of Future) of Personalized Prescription in Psychiatry

Rapid technological advances in genetics have created conceptual chaos regarding the genetics of drug response. Terms for differing concepts are used interchangeably: pharmacogenetics with pharmacogenomics, personalized medicine with personalized prescription. Biomarker has many definitions. The author prefers the concept of personalized prescription and uses it with implications beyond pharmacogenetics by considering all scientific information valid for prescribing medication. Genetics may not be crucial for all drugs. In this comprehensive view, clinicians must consider genetic, environmental and personal variables when prescribing medication and incorporate some basic pharmacological principles: (1) safety and efficacy, (2) pharmacokinetics and pharmacodynamics, (3) therapeutic window and prescriber\u27s role, and (4) idiosyncratic and dose-related adverse drug reactions. Personalized prescription in the clinical environment can be expressed in two main ways: as personalized selection of the drug and as personalized dosing. The future, or lack of future, of personalized drug selection and of personalized dosing in psychiatry is reviewed. Currently, the author thinks that, in psychiatry, pharmacogenetic tests have some potential in two areas: (1) excluding some drugs for some unusual patients (HLA-B*1502 genotyping in Asians for carbamazepine), and (2) using pharmacokinetic genes for personalizing dosing in narrow therapeutic window drugs. In the short term, there is dubious potential for other pharmacogenetic tests and no potential for pharmacogenetic testing to ascertain the best drug for each patient. Personalized dosing has immediate application if one understands it as the use of our current scientific knowledge of genetic, environmental and personal variables to determine dosing; its sole requirement is well-trained psychiatrists

Glucuronidation Enzymes, Genes and Psychiatry

The phase I cytochrome P450 (CYP) isoenzymes have received substantial attention in the pharmacogenetic literature. Researchers are beginning to examine the role of the phase II UDP-glucuronosyltransferase (UGT) enzymes, which produce products that are more water-soluble, less toxic and more readily excreted than the parent compounds. Several reasons may have contributed to neglect of UGTs (compared to CYPs) including: (1) the overlapping activity of UGTs and lack of selective probes; (2) the complexity of the glucuronidation cycle; and (3) the difficulty in developing analytic methods to measure glucuronides. Current CYP knowledge is used as a model to predict advances in UGT knowledge. At least 24 different UGT human genes have been identified and are classified in two families (UGT1 and UGT2) based on sequence homology. The UGT1A subfamily (genes located on chromosome 2) glucuronidates bilirubin, thyroid hormones, and some medications. UGT1A4 metabolizes tricyclic antidepressants and some antipsychotics. The UGT2B subfamily (genes located on chromosome 6) glucuronidates sexual steroids and bile acids. Oxazepam and lorazepam are mainly metabolized by glucuronidation. Anti-epileptics with mood-stabilizing properties are frequently metabolized by UGTs. Opioid and nicotine addiction may also be influenced by glucuronidation. Glucuronidation of serotonin may be important during fetal development. UGTs appear to be in small concentrations in brain tissue (and higher concentrations at brain capillaries). However, UGTs may be localized in certain brain areas to provide a neuroprotective function. This review illustrates the importance of glucuronidation and the implications for psychiatry

The Effects of Antiepileptic Inducers in Neuropsychopharmacology, a Neglected Issue. Part I: A Summary of the Current State for Clinicians

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. This is part i of a comprehensive review on antiepileptic drug (AED) inducers using both mechanistic pharmacological and evidence-based medicine to provide practical recommendations to neurologists and psychiatrists concerning how to control for them. Carbamazepine, phenobarbital and phenytoin, are clinically relevant AED inducers; correction factors were calculated for studied induced drugs. These correction factors are rough simplifications for orienting clinicians, since there is great variability in the population regarding inductive effects. As new information is published, the correction factors may need to be modified. Some of the correction factors are so high that the drugs (e.g., bupropion, quetiapine or lurasidone) should not co-prescribed with potent inducers. Clobazam, eslicarbazepine, felbamate, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and valproic acid are grouped as mild inducers which may (i) be inducers only in high doses; (ii) frequently combine with inhibitory properties; and (iii) take months to reach maximum effects or de-induction, definitively longer than the potent inducers. Potent inducers, definitively, and mild inducers, possibly, have relevant effects in the endogenous metabolism of (i) sexual hormones, (ii) vitamin D, (iii) thyroid hormones, (iv) lipid metabolism, and (v) folic acid

One Hundred Years of Limited Impact of Jaspers’ General Psychopathology on US Psychiatry

Jaspers, a German psychiatrist, published General Psychopathology in 1913. Jaspers, Schneider, and Mayer-Gross were members of the Heidelberg school. General Psychopathology, indirectly through Schneider’s and Mayer-Gross’ textbooks and directly by its English translation in 1963, led to a narrow set of schizophrenia criteria in the United Kingdom. General Psychopathology had very limited direct impact on US psychiatry, which adopted a broader schizophrenia definition. The difference between UK and US schizophrenia was a key element in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, and the neo-Kraepelinian revolution. General Psychopathology contains two essential interrelated ideas: a) psychiatry is a hybrid scientific discipline that must combine natural and social science methods that provide an explanation of illness that follows the medical model and an understanding of psychiatric abnormalities that are variations of human living, respectively, and b) psychiatric disorders are heterogeneous. Berrios’ ideas on the hybridity of psychiatry in the United Kingdom and McHugh’s ideas on psychiatric diagnoses in the United States can be considered neo-Jasperian approaches because they further elaborate these two Jasperian concepts in the late 20th century

REFLECTIONS ON THE COMPLEX HISTORY OF THE CONCEPT OF CLOZAPINE-INDUCED INFLAMMATION DURING TITRATION

Clozapine was synthesized in 1958. The Food and Drug Administration approved it in 1989 when comprehensive pharmacokinetic studies were not required and it was not known that clozapine was metabolized by the cytochrome P450 1A2 (CYP1A2). Currently it is known that clozapine personalized dosing may be influenced by one’s DNA ancestry (African, European and/or Asian/Indigenous American), sex/smoking subgroup, and the presence/absence of genetic/non-genetic poor metabolizer (PM) status. The literature does not properly reflect the concept of "clozapine-induced inflammation" during rapid titration. Elaborating upon this concept, this historical review discusses: 1) clozapine-induced fever, 2) the effects of inflammation on clozapine metabolism, 3) clozapine-induced myocarditis, 4) other clozapine-induced inflammations, 4) current support for “clozapine-induced inflammation” as a hypersensitivity reaction, 5) the difficulty in addressing such a concept to a readership with diverse beliefs about it and 6) the limitations of this review in convincing skeptics. Clozapine-induced fever in the absence of any concomitant infection was first described in 1972 and is a mild form of "clozapine-induced inflammation" during rapid titration, which also includes myocarditis and other localized inflammations. They may be part of a hypersensitivity reaction that has 3 phases. In the first phase, the titration is too fast for a specific patient; either the psychiatrist was too aggressive in titrating, and/or the patient is a clozapine PM. This situation leads to a release of cytokines. In the second phase, a positive feedback loop develops; the cytokines inhibit CYP1A2, which further increases plasma clozapine concentrations. In the third phase, if the titration continues, the inflammation becomes complicated by the development of an auto-immune phenomenon leading to localized inflammation. Skeptical readers are challenged to try: 1) 6 titrations proposed for stratified dosing and 2) c-reactive protein (CRP) monitoring for personalized dosing in the absence of genetic testing for clozapine PM status

The Effects of Antiepileptic Inducers in Neuropsychopharmacology, a Neglected Issue. Part II: Pharmacological Issues and Further Understanding

The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P-glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnaneX receptors). Although parti provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described