Psychotropic Dosing in the Medically Ill

Psychotropic Dosing in the Medically Ill requires different dosing principles 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, nortriptyline
    • Sertraline, escitalopram, trazodone, and mirtazapine can also be used.
  • 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]
  • Citalopram is the agent of choice in patients taking warfarin
  • Amitriptyline may be used for post-stroke pain
  • High psychiatric comorbidity
    • Psychosis and depression are risk factors for seizures
  • Antidepressant and antipsychotics can cause hyponatraemia, which may further lower the seizure threshold
  • More sedating agents more likely to induce seizures
  • Anticonvulsant drugs 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
    • Conduction disturbances and arrhythmias
  • At risk patients include those with:
    • Unstable coronary artery disease, congestive heart failure, conduction abnormalities, 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
• Sertraline: drug of choice in post-MI depression[4]
Other Antidepressants • Venlafaxine, duloxetine: may affect blood pressure or heart rate
• Trazodone: reports of orthostatic
hypotension, arrhythmias, QT prolongation
• Bupropion: Elevates blood pressure
• 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
• 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
• ECG in at risk patients
Mood stabilisers • Lithium: non specific ECG changes, uncommon: sinus node dysfunction, AV block, QTc prolongation, decreased clearance in CCF
• Valproic acid is safe
• Carbamazepine: cardiotoxic, AV conduction disturbances
• Lamotrigine: clinically insignificant PR prolongation
Dementia medications • Cholinesterase inhibitors: vagotonic effects avoid in patients with conductionabnormalities and unexplained syncopal episodes
• Memantine: rarely causes bradycardia
Stimulants • Increase heart rate and blood pressure
• Methylphenidate and dextroamphetamine no significant cardiovascular effects in 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
  • Antidepressants: generally safe
  • Benzodiazepines: respiratory depressant
  • Lorazepam, oxazepam, temazepam, agents of choice in COPD
  • All benzodiazepines are contraindicated in sleep apnea
    • Non-benzodiazepine hypnotics, ramelteon, buspirone are safer
  • Antipsychotics: watch out for extrapydramidal symptoms including laryngeal dystonia, tardive dyskinesia
    • Clozapine: respiratory arrest or depression, allergic asthma
  • 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 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 and chlorpromazine
  • Perform routine liver function tests
  • 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

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 more than 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
  • Antidepressants: SSRIs first line
  • Fluoxetine and sertraline reduce HbA1c
  • Avoid TCAs
  • SNRIs used in the treatment of diabetes neuropathy
  • Antipsychotics: Be aware of the metabolic complications
  • Minimal weight gain for ziprasidone and aripiprazole
  • Mirtazapine has the lowest risk for GI bleeding based on existing literature

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.[5]
• 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 medications
• Hepatotoxicity from second-generation antipsychotics is rare
Mood Stabilizers • Carbamazepine and valproate relatively contra-indicated
• Gabapentin 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
Dementia medications • Donepezil, galantamine, rivastigmine should be used with caution
• Memantine mainly renally eliminated 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 starget dose
Citalopram, escitalopram No reduction or minimal reductionNo reduction or minimal reduction
Bupropion Reduced dose in Child Class A (least severe liver disease)
Venlafaxine >50% reduction in moderate liver disease
Desvenlafaxine No reduction (renally excreted)No reduction (renally excreted)
Duloxetine Health Canada and FDA warning for patient's with liver disease
Levomilnacipran No reductionNo reduction
Vortioxetine No reductionNo reduction
Valproate Reduced dose (monitor LFTs); contraindicated in severe liver disease
Carbamazepine Reduced dose
Lamotrigine Reduced dose
Gabapentin No reduction (renally excreted)No reduction (renally excreted)
Lithium No reduction (renally excreted)No reduction (renally excreted)
Risperidone, quetiapine Reduced dose
Olanzapine, ziprasidone, aripiprazole No reduction in mild-moderate liver disease
Paliperidone No reduction (renally excreted)No reduction (renally excreted)
Donepezil, galantamine, rivastigmine Reduced dose and use with caution
Memantine No reduction (renally excreted)No reduction (renally excreted)
  • Renal disease alters absorption, distribution and protein binding, and reduces the capacity to excrete drugs
  • Drugs requiring dose reduction include: lithium, gabapentin, pregabalin, memantine, paliperidone, paroxetine, desvenlafaxine, topiramate, and venlafaxine
    • Classify stage of impairment using GFR
    • A general rule is to give only 2/3 of dose in renal impairment
  • Drugs removed by dialysis: lithium, gabapentin, pregabalin, valproate, topiramate, and levetiracetam
    • Assume older adults have some degree of renal impairment
  • Avoid nephrotoxic drugs, extensively renally cleared drugs (sulpiride, amisulpiride, lithium)
  • Avoid long-acting drugs, those with anticholinergic side effects, 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[6]
• Avoid: amisulpiride and sulpiride
• Avoid highly anticholinergic agents
Anxiolytics and Sedative Hypnotics • Monitor for excessive sedation
• Lorazepam, oxazepam, zopiclone are preferred agents
• Dose reduction required in ESRD
• Avoid barbiturates, cause osteomalacia and sedation
• Do not use diazepam due to its long half life
Mood Stabilizers[7] • 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, lamotrigine, start low dose increase slowly
Dementia medications • Limited data
• Rivastigmine first line
• Avoid galantamine in moderate to severe renal insufficiency
• Reduce dose of memantine
Gabapentinoids • Gabapentin and pregabalin are significantly renally excreted
Stimulants • No dose reduction required
  • 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 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.[8][9]

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