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)
    • Conduction disturbances and arrhythmias
  • At risk patients include those with:
    • Unstable coronary artery disease, congestive heart failure, conduction abnormalities, and orthostatic hypotension

Medication Classes in Cardiovascular Disease

Class Suggestion
Tricyclic Antidepressants • Avoid in patients with cardiac disease
• Increase heart rate, cause postural hypotension, slow cardiac conduction and have class I anti-arrhythmic activity
• Cardiotoxic in overdose
SSRIs Fluoxetine: mild bradycardia in elderly with pre-existing arrhythmias
Citalopram: dose dependant QTc interval prolongation, avoid doses > 40mg
Escitalopram: similar profile, but thought to be less risky
Sertraline: drug of choice in post-MI depression[4]
Other Antidepressants Venlafaxine, duloxetine, bupropion: may affect blood pressure or heart rate
Trazodone: reports of orthostatic hypotension, arrhythmias, QT prolongation
Mirtazapine: no significant effects post-MI
• Mianserin: low cardiotoxicity
Antipsychotics • Congestive heart failure: avoid agents that cause postural hypotension (low potency, clozapine, quetiapine)
• Increased risk of sudden cardiac death[5]
• Highest risk of prolonging QTc: pimozide, thioridazine, droperidol, sertindole, ziprasidone, quetiapine, haloperidol
• Lowest effect on QTc: aripiprazole, paliperidone, clozapine, olanzapine, risperidone, sulpiride
Clozapine: myocarditis, cardiomyopathy
• Order an ECG in at risk patients
Mood stabilizers Lithium: non-specific ECG changes, uncommon: sinus node dysfunction, AV block, QTc prolongation, decreased clearance in CHF
Valproic acid is safe
Carbamazepine: cardiotoxic, AV conduction disturbances
Lamotrigine: clinically insignificant PR prolongation
Dementia medications • Cholinesterase inhibitors have vagotonic effects, avoid in patients with bradycardia (HR<50), conduction abnormalities, and unexplained syncopal episodes
Memantine: rarely causes bradycardia
Stimulants • Increase heart rate and blood pressure
Methylphenidate and dextroamphetamine have no significant cardiovascular effects at low doses
• Contraindicated: structural cardiac abnormalities, cardiomyopathy, coronary artery disease, cardiac rhythm abnormalities
Modafinil increases BP in non-cardiac patients
Atomoxetine increases heart rate, blood pressure in non-cardiac patients, avoid in cardiac patients

Medication Classes in Respiratory Disease

Class Suggestion
Antidepressants Antidepressants are generally safe
Antipsychotics Antipsychotics may cause extrapydramidal symptoms including laryngeal dystonia or tardive dyskinesia
Clozapine carries a risk for respiratory arrest or depression,[6] and allergic asthma[7]
Benzodiazepines Benzodiazepines should be avoided or reduced as they are a respiratory depressant
Lorazepam, oxazepam, and temazepam are the agents of choice if they must be used in COPD
• All benzodiazepines are a relative contraindication in sleep apnea[8]
• Non-benzodiazepine hypnotics such as ramelteon or buspirone are safer
Dementia medications • Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) should be used with caution in individuals with COPD, as it may exacerbate COPD
  • 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

Medication Classes in Hepatic Impairment

Class Suggestion
Antidepressants • Anticholinergic TCAs can exacerbate hepatic encephalopathy
Citalopram, paroxetine, sertraline, and fluoxetine have all been used safely in patients with hepatitis C
• Hepatotoxicity is a rare side effect of many antidepressants
Duloxetine is hepatotoxic in patients with liver disease
Bupropion and trazodone should be reduced in dose.[9]
• Monitor QTc
Antipsychotics Haloperidol most commonly chosen agent
• Sulpiride/amisulpiride are also safe options
• Avoid chlorpromazine
Clozapine is contraindicated in active liver disease, progressive liver disease and hepatic failure
• Avoid low potency antipsychotics
• Hepatotoxicity from second-generation (atypical) antipsychotics is rare
Mood Stabilizers Carbamazepine and valproate are relatively contraindicated
Gabapentin is generally safe as it is renally excreted
Lithium may require dosage adjustment because of fluid shifts associated with ascites
Lamotrigine dose should be reduced according to severity of hepatic impairment
Benzodiazepines Lorazepam, oxazepam, and temazepam are metabolized by phase II conjugation and have short half lives with no active metabolites, thus they are preferred agents in patients with hepatic disease
• However, all benzodiazepines should be avoided in patients at risk of developing hepatic encephalopathy
Dementia medications • Acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) should be used with caution
Memantine is mainly renally eliminated so no dose reduction required

Hepatic Adjustments for Common Psychotropics

Adapted from: Crone, C. et al. (2006). An overview of psychiatric issues in liver disease for the consultation–liaison psychiatrist. Psychosomatics, 47(3), 188-205.
Medication Hepatic Dose Adjustment
Alprazolam, diazepam, clonazepam 50% reduction
Lorazepam, oxazepam, temazepam No reduction needed, but avoid in hepatic encephalopathy
Paroxetine, fluoxetine, fluvoxamine, sertraline Lower starting and target dose
Citalopram, escitalopram No reduction or minimal reduction
Bupropion Reduced dose in Child-Pugh Class A (least severe liver disease)
Venlafaxine >50% reduction in moderate liver disease
Desvenlafaxine No reduction (renally excreted)
Duloxetine Health Canada and FDA warning for patient's with liver disease
Levomilnacipran No reduction
Vortioxetine No reduction
Valproate Reduced dose (monitor LFTs); contraindicated in severe liver disease
Carbamazepine Reduced dose
Lamotrigine Reduced dose
Gabapentin No reduction (renally excreted)
Lithium No reduction (renally excreted)
Risperidone, quetiapine Reduced dose
Olanzapine, ziprasidone, aripiprazole No reduction in mild-moderate liver disease
Paliperidone No reduction (renally excreted)
Donepezil, galantamine, rivastigmine Reduced dose and use with caution
Memantine No reduction (renally excreted)
  • 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
  • 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 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.

Medication Classes in Renal Impairment

Class Suggestion
Antidepressants • Virtually all antidepressants can be used
• SSRIs first line: sertraline, citalopram
TCAs: Nortriptyline is preferred
• Reduce dose: venlafaxine, desvenlafaxine, bupropion, paroxetine, mirtazapine, and reboxetine
Antipsychotics • All antipsychotics can be used
• First line: haloperidol 2-6mg, olanzapine 5mg (both undergo minimal renal excretion)
• Reduce dose: risperidone and its metabolite paliperidone (9-hydroxyrisperidone) is renally excreted[11]
• Avoid amisulpiride and sulpiride
• Avoid highly anticholinergic agents
Benzodiazepines and Z-Drugs • Monitor for excessive sedation
Lorazepam, oxazepam, zopiclone are preferred agents
• Dose reduction required in end stage renal disease (ESRD)
• Avoid barbiturates, which can cause osteomalacia and sedation
• Do not use diazepam due to its long half life
Mood Stabilizers[12] Lithium is entirely excreted by kidneys, and thus contraindicated in acute renal failure but not chronic renal failure
• Lithium completely is also dialysed, give single oral dose after dialysis, check levels 2-3 hours after dialysis
• First line: valproate, carbamazepine, carbamazepine, start at a low dose and increase slowly
Dementia medications • Limited data, but donepezil is generally thought to be safest out of all acetylcholinesterase inhibitors in renal impairment.[13]
Rivastigmine can be used, but should be avoided in severe renal impairment.
• Avoid galantamine in moderate to severe renal impairment
• Reduce dose of memantine depending on severity of kidney impairment:
– Severe impairment (creatinine clearance 5 to 29 mL/min) maximum dose 10mg daily.
– Avoid if creatinine clearance less than 5ml/min
Gabapentinoids Gabapentin and pregabalin are significantly renally excreted
Stimulants • No dose reduction required
  • Antidepressants: SSRIs are first line
    • Fluoxetine and sertraline may reduce HbA1c[14]
    • Avoid TCAs
    • 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.

Choosing Antidepressants in Breast Cancer

Adapted from: Desmarais, J. E. et al. (2009). Interactions between tamoxifen and antidepressants via cytochrome P450 2D6. The Journal of clinical psychiatry, 70(12), 1688-1697.
Drug Effect on CYP2D6 Advice
Venlafaxine Minimal Safest choice if taken with tamoxifen
Desvenlafaxine, mirtazapine Direct studies with tamoxifen are lacking, but effect on endoxifen levels should be minimal. Also a reasonable choice
Citalopram, escitalopram Mild Secondary choice if above are not options. Only citalopram and sertraline have been studied directly with tamoxifen, so risk of reducing levels of endoxifen should be weighed against benefits of antidepressants.
Duloxetine, sertraline, fluvoxamine Moderate Weigh risks carefully
Paroxetine, fluoxetine, bupropion Strong Avoid if taking tamoxifen
  • 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:
  • 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.

Organ Transplantation

Drug Interaction
Desipramine, haloperidol, fluoxetine, fluvoxamine, sertraline, trazodone Increases cyclosporine and tacrolimus levels, with potential to cause toxicity