- Last edited on April 3, 2023
Psychotropic Dosing in the Medically Ill
Primer
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.
Central Nervous System
General Principles
- 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
Stroke
See main article: Stroke
- 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
Seizures
See main article: Approach to Seizures
- 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)
Cardiac
General Principles
See main article: QT (QTc) Prolongation and Monitoring
- 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
Cardiac Considerations for Common Psychotropics
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, QTc prolongation (unlikely)[5] • 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[6] • 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 |
Respiratory Disease
Respiratory Considerations for Common Psychotropics
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,[7] and allergic asthma[8] |
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[9] • 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 |
Hepatic/GI
General Principles
- 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
Hepatic Considerations for Common Psychotropics
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.[10] • 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) |
Drug-Induced Hepatotoxicity
- 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
GI Bleeding
See main article: SSRI and SNRI Bleeding Risks
Renal
General Principles
See also:
- 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.
Renal Considerations for Common Psychotropics
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[12] • 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[13] | • 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.[14] • 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 |
Diabetes Mellitus
- Antidepressants: SSRIs are first line
- Antipsychotics: be aware of the metabolic complications
- Less risk for weight gain for ziprasidone and aripiprazole (but not always!)
HIV
See main articles: Human Immunodeficiency Virus (HIV) and Cytochrome (CYP) P450 Metabolism
- 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.
Cancer
Breast
- Paroxetine, fluoxetine, bupropion, and duloxetine have been shown to inhibit CYP2D6 and interfere with tamoxifen treatment for individuals with breast cancer.[16][17]
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
- 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[18]), serotonin norepinephrine reuptake inhibitors (duloxetine, venlafaxine), and even selective serotonin reuptake inhibitors (fluoxetine[19]) 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.
Organ Transplantation
Organ Transplantation
Drug | Interaction |
---|---|
Desipramine, haloperidol, fluoxetine, fluvoxamine, sertraline, trazodone | Increases cyclosporine and tacrolimus levels, with potential to cause toxicity |
Resources
References
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