Psychotropic Dosing in the Medically Ill

Psychotropic Dosing in the Medically Ill requires different prescribing principles and considerations compared to healthy individuals. Individuals with cardiac, central nervous system, respiratory, gastrointestinal, and renal impairments all have different dosing considerations.

• Individuals with CNS diseases, such as traumatic brain injuries, seizures, and tumours generally have:
  • Lower threshold for CNS side effects of medications
  • Higher risk for orthostatic hypotension
  • Other co-morbid cardiac diseases or diabetes

• For existing post-stroke depression, the most studied medications are fluoxetine, citalopram, and nortriptyline
  • Sertraline, escitalopram, trazodone, and mirtazapine can also be used.
  • Citalopram is the agent of choice in patients taking warfarin
  • Amitriptyline may be used for post-stroke pain
• Although antidepressants were previously used as prophylaxis to try to prevent post-stroke depression, recent studies have shown no benefits and in fact increased risk with antidepressant treatment.^[1][2][3]

• Individuals with seizures often have high psychiatric comorbidity
  • Psychosis and depression are risk factors for seizures
• Antidepressant and antipsychotics can cause hyponatraemia, which may further lower the seizure threshold
• Sedating psychotropics are more likely to induce seizures
• Anticonvulsant drugs can be associated with new-onset depression and psychosis
• Be aware of drug-drug interactions (e.g. - carbamazepine, valproate, lamotrigine)

• Potential cardiovascular side effects of psychotropic medications include:
  • Orthostatic hypotension
  • Changes in heart rate (tachycardia or bradycardia)
  • QTc prolongation
  • Conduction disturbances and arrhythmias
• At risk patients include those with:
  • Unstable coronary artery disease, congestive heart failure, conduction abnormalities, and orthostatic hypotension

• Individuals with gastrointestinal disorders or hepatic insufficiency will have:
  • Reduced capacity to metabolize biological waste and drugs, which can result in hepatic encephalopathy
  • Reduced ability to synthesize plasma proteins and clotting factors, which can affect protein binding (albumin) and bleeding times
  • Reduced hepatic blood flow, which can reduce first-pass metabolism and result in elevated plasma levels of drug
• In patients with gastric absorption issues, (e.g. - short-gut syndrome), medications such as escitalopram are better than bupropion, quetiapine, and desvenlafaxine (these all have hard coatings that make absorption more difficult).
• Prescribe as few drugs as possible and use lower starting doses
• Avoid drugs that are very sedating or constipating
• Avoid drugs that are hepatotoxic in their own right, such as MAOIs or chlorpromazine
• Order routine liver function tests

• Psychotropic drug-induced hepatotoxicity are rare and usually idiosyncratic. Hepatotoxicity is usually defined as:
  • ALT > 3 times the upper limit of normal combined with a serum bilirubin > 2 times the upper limit of normal
  • Risk factors include: older age, female gender, alcohol consumption, obesity, pre-existing liver disease, genetic predisposition, co-prescribing of CYP enzyme-inducing drugs

• Mirtazapine and bupropion have the lowest risk for GI bleeding based on existing literature.^[11]

• Renal disease alters absorption, distribution and protein binding, and reduces the capacity to excrete drugs
• Assume all older adults have some degree of renal impairment
  • A general rule is to give only 2/3 of the regular dose in renal impairment
• Drugs requiring dose reduction include: lithium, gabapentin, pregabalin, memantine, paliperidone, paroxetine, desvenlafaxine, topiramate, and venlafaxine
• Drugs that are removed by dialysis include: lithium, gabapentin, pregabalin, valproate, topiramate, and levetiracetam
• Avoid nephrotoxic drugs, extensively renally cleared drugs (sulpiride, amisulpiride, lithium)
• Avoid long-acting drugs, those with anticholinergic side effects, and those that prolong QTc interval due to decreased rate of clearance.

• Antidepressants: SSRIs are first line
  • Fluoxetine and sertraline may reduce HbA1c^[15]
  • Fluoxetine may produce hypoglycemia in patients with diabetes who use insulin.^[16][17]
  • Avoid tricyclic antidepressants, as TCAs might induce a decrease in glucose tolerance and worsen the control of diabetic patients.^[18]
  • SNRIs can be used in the treatment of diabetes neuropathy
• Antipsychotics: be aware of the metabolic complications
  • Less risk for weight gain for ziprasidone and aripiprazole (but not always!)

• Patients on protease inhibitors (e.g. - liponavir-ritonivir) need to have dose adjustments considered
• Protease inhibitors are potent inhibitors of CYP3A4
  • Remember that CYP3A4 metabolizes all non-LOT (lorazepam, oxazepam, tamazepam) benzodiazepines, quetiapine, and trazodone.

• Paroxetine, fluoxetine, bupropion, and duloxetine have been shown to inhibit CYP2D6 and interfere with tamoxifen treatment for individuals with breast cancer.^[19][20]

• Pheochromocytoma is a rare neuroendocrine tumour of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. These tumours can produce and release massive amounts of catecholamines, metanephrines, or methoxytyramin which can cause hypertension, tachycardia, and diaphoresis.
• Pheochromocytomas can be pharmacologically unmasked or provoked by psychotropic (and non-psychotropic) medications, specifically:
  • Tricyclic antidepressants (including amitriptyline, nortriptyline, desipramine^[21]), serotonin norepinephrine reuptake inhibitors (duloxetine, venlafaxine), and even selective serotonin reuptake inhibitors (fluoxetine^[22]) can lead to increased concentrations of norepinephrine and epinephrine in the synaptic clefts.
  • Monoamine oxidase inhibitors (MAOIs) can block the conversion of norepinephrine and epinephrine to dihydroxyphenylglycol (DHPG), leading to increased concentrations and availability of these two catecholamines.
• In an individual suspected of having a pheochromocytoma, it is critically important that they be discontinued off the above medications, and have a clinical work up.

• Rosenblat, J. D., Kurdyak, P., Cosci, F., Berk, M., Maes, M., Brunoni, A. R., ... & Carvalho, A. F. (2020). Depression in the medically ill. Australian & New Zealand Journal of Psychiatry, 54(4), 346-366.