(1)
Departments of Internal Medicine & Psychiatry, Yale University School of Medicine, New Haven, CT, USA
This chapter is an overview of general principles of prescribing psychotropic medications in people with preexisting medical conditions. Effects of failure in major organ systems that affect drug absorption, metabolism, and excretion are reviewed.
General Principles
Whenever a new psychotropic medication is prescribed or a patient’s physical health condition changes while on chronic psychotropic treatment, the following factors should be considered.
Can the underlying medical illness cause or exacerbate the presenting psychiatric symptomatology (e.g., hypothyroidism causing fatigue and depression)?
Do medications used to treat the underlying medical illness have potential for aggravating the psychiatric illness (e.g., corticosteroids and depression, mania or psychosis)?
Can the underlying medical condition affect the availability, metabolism, or elimination of the psychotropic medication (e.g., reduction of drug absorption after bariatric surgery, changes in protein binding in pregnancy, reduction of drug elimination in end-stage liver disease)?
Does any underlying genetic variability affect drug metabolism (e.g., more whites than other races are poor metabolizers of CYP2D6 an enzyme that metabolizes many psychotropic medications; more people of Southeast Asian descent have a particular variation of the major histocompatibility complex gene (HLA-B), namely, HLA-B* 1502, that increases risk for Steven–Johnsons syndrome or toxic epidermal necrolysis when treated with carbamazepine)?
Does the psychotropic medication cause harm to the underlying or newly developed medical condition (e.g., atypical antipsychotics and diabetes; drugs with teratogenic potential and pregnancy)?
Do the medications used to treat the medical illness interact with the psychotropic medication causing (a) change in serum level of an agent with a narrow therapeutic index (e.g., lithium toxicity with lithium and diuretics), (b) a serious adverse reaction during combination therapy (e.g., serotonin syndrome with a serotonergic antidepressant and triptans), and (c) loss of efficacy of medication (e.g., decreased efficacy of both phenytoin and carbamazepine when used in combination).
The appendix lists common psychiatric adverse effects of nonpsychotropic medications as well as common drug–drug interactions between psychotropic and nonpsychotropic medications.
Liver Disease
Liver disease affects drug pharmacokinetics in the following ways.
Decreased synthesis of plasma proteins leading to higher free drug plasma levels
Decreased liver enzyme synthesis leading to impaired drug metabolism
Decreased blood flow to liver leading to reduced drug elimination
Peripheral edema leading to increased volume of distribution
Vascular congestion and portal hypertension leading to decreased absorption of orally administered drugs
Among all these pathways, decreased liver enzyme synthesis is what causes significant change in psychotropic drug pharmacokinetics. A majority of psychotropic medications are metabolized and excreted through the liver. Hence, with a decrease in liver enzyme synthesis, drug metabolism is reduced requiring a reduction in dose of many psychotropic medications. The table lists the few medications not metabolized in the liver.
Psychotropic drugs not metabolized by the liver
Lithium |
Gabapentin |
Pregabalin |
Topiramate |
Liver metabolizes drugs through two phases. Phase I metabolism produces active metabolites from parent drugs by oxidation, reduction, or hydrolysis. Cytochrome P450 is the major isoenzyme family metabolizing the majority of psychotropic medications and the two main isoenzymes are CYP3A4 and CYP2D6.
Phase II metabolism prepares drug products for elimination by glucuronidation, acetylation, or sulfation. The major family of enzymes involved in psychotropic drug metabolism is the uridine glucuronyltransferases (mainly 2B7). Phase II metabolism is generally preserved in liver cirrhosis. Some medications that undergo almost exclusively phase II metabolism are lorazepam, oxazepam, and temazepam [1]. These benzodiazepines are preferentially used in patients with liver disease.
There are many substances, including prescribed medications, that affect P450 activity and thus alter levels of other drugs. Some common P450 inhibitors and inducers, including psychotropic medications, are listed in the table.
Substances affecting P450 activity
P450 inhibitors (increase medication levels) |
Ketoconazole (2C9) |
Amiodarone (1A2, 2C9, 2D6) |
Isoniazid (2C19) |
Diltiazem (3A4) |
Grape fruit juice (1A2, 3A4) |
Omeprazole (2C19) |
Many protease inhibitors (3A4) |
Quinidine (2D6) |
Ciprofloxacin (1A2) |
Fluoxetine (2C9) |
Fluvoxamine (1A2) |
Paroxetine (2D6) |
Ritonavir (2C9, 2C19, 2D6, 3A4) |
P450 inducers (decrease medication levels) |
Rifampin (2C9, 2C19) |
Phenytoin (2C9, 2C19) |
Carbamazepine (1A2, 2C9, 2C19) |
St. Johns wort (3A4) |
Cigarette smoking (polycyclic aromatic hydrocarbons) (1A1, 1A2) |
Medications with long half-lives, active metabolites, and extended release formulations may have less predictable pharmacokinetics and are less preferable in liver disease.
In general, it is prudent to start any medication at a lower dose and titrate slowly in the presence of liver disease. Medications to be used with particular caution are listed in the table.
Psychotropic medication categories to be used with caution in liver disease
Category | Mechanism | Example |
|---|---|---|
Drugs with potential for hepatotoxicity | Carry an increased risk with preexisting liver disease | Carbamazepine, valproate, duloxetine |
Drugs with sedative and anticholinergic properties | May precipitate hepatic encephalopathy due to intestinal stasis and central effects | Low-potency antipsychotics, benzodiazepines |
Drugs at risk for causing cytopenias | May worsen low blood counts seen in liver disease | Carbamazepine, antipsychotics
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