Prescribing Psychiatric Medications for Patients with Medical Problems

One of the most difficult aspects of using psychiatric medication is the relative dearth of evidence for using these medications in patients with complex medical histories. Clinical trials often exclude patients with complex medical histories which makes choosing medications difficult. Despite the lack of significant data, case reports, case series, and small studies (as well as a few large studies) continue to provide guidance on the use of psychotropic medications in medically ill patients.

Below we review important concepts for prescribing psychotropic medications in patients with Liver Disease, Cardiovascular Disease, Renal Disease, and Neurological Disease.

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  • Liver Disease
  • Cardiovascular Disease
  • Renal Disease
  • Neurological Disease

Pharmacokinetic and Pharmacodynamic Considerations in Liver Disease

  • The Bioavailability (BA) of a drug is the proportion of drug that makes its way to the systemic circulation
  • For drugs given by mouth (PO), bioavailability (i.e., how much of the drug makes it to the systemic circulation) is influenced by gastrointestinal functioning and first pass metabolism
  • Recall that the small intestine is the major site of absorption for most orally administered drugs
  • Many patients with liver disease suffer from gastroparesis or impaired GI motility, which delays drug delivery to the intestine
  • Patients with cirrhosis, portal hypertension, and vascular congestion usually absorb drugs from the intestine much slower
  • Hepatic insufficiency typically decreases first pass metabolism which can result in increased plasma drug levels
  • Quantitative changes in plasma protein levels due to hepatic insufficiency alters protein binding and free drug levels (but this is probably clinically insignificant)
  • Ascites and peripheral edema increase the volume of distribution of hydrophilic (i.e., water soluble) drugs which may result in overall decreased plasma drug concentrations
  • Therapeutic drug monitoring may be valuable but should be interpreted with caution because changes in protein binding may lead to falsely low estimates (always try to measure free drug levels!)
  • Drugs with a small therapeutic window (lithium) should be used with caution
  • Drugs with multi step biotransformation or those with active metabolites (amitriptyline, imipramine, venlafaxine, bupropion) are more complicated to dose
  • Generally avoid drugs with long half-lives (e.g., fluoxetine) or extended/slow-release formulations due to unpredictable pharmacokinetics in hepatic insufficiency
  • Caution with hydrophilic drugs and/or active metabolites that distribute in total body water as paracentesis, diuresis, and fluid loss can cause rapid changes in drug concentration (due to rapid fluid shifts)

Adjust dose according to the Child-Pugh Score

(See Bottom of The Page)

  • Score A (5-6 points): use 75-100% regular dose
  • Score B (7-9 points): use 50% regular dose
  • Score C (10-15 points): CAUTION/AVOID USE 

Medications Requiring Dose Adjustments in Liver Disease

MedicationComments
SSRIsExtensively metabolized; decreased clearance and prolonged half-life. Initial dose should be reduced by 50%, with potentially longer dosing intervals between doses. Target doses are typically substantially lower than usual
MAOIsPotentially hepatotoxic. No dosing guidelines.
TCAs Extensively metabolized. Potentially serious hepatic effects. No dosing guidelines.
BupropionExtensively metabolized; decreased clearance. Reduce dose/frequency. In severe Cirrhosis, do not exceed 75mg/day for conventional tablets or 100mg/day for sustained release formulations
Desvenlafaxine Primarily metabolized by conjugation. No adjustment in starting dose needed in HI. Do not exceed 100mg/day in severe HI.
Venlafaxine Decreased clearance of venlafaxine and its active metabolite. Reduce dosage by 50% in mild to moderate HI, per manufacturer.
Duloxetine Extensively metabolized; reduced metabolism and elimination. Do not use in patients with any HI.
MirtazapineExtensively metabolized; decreased clearance. No dosing guidelines.
TrazodoneExtensively metabolized. No dosing guidelines.
ClozapineExtensively metabolized. Discontinue in patients with marked transaminase elevations or jaundice. No dosing guidelines.
Paliperidone Primarily renally excreted. No dosage adjustment needed.
Risperidone Extensively metabolized. Free fraction increased 35%. Starting dosage and dose increments not to exceed 0.5mg twice daily. Increases >1.5mg twice daily should be made at intervals of > 1 week.
Quetiapine Extensively metabolized. Clearance decreased 30%. Start at 25mg/day and increase by 25-50mg/day.
Ziprasidone Extensively metabolized; increased half-life and serum level in mild to moderate HI. In spite of this, manufacturer recommends no dosage adjustment.
TypicalsAll metabolized in liver. No specific dosing recommendations. Avoid phenothiazines (thioridazine, trifluoperazine, thorazine) due to cholestatic hepatotoxicity. Reduce starting dose of all typicals and titrate slowly.
Alprazolam Decreased metabolism and increased half-life. Reduce dosage by 50%. Avoid use in patients with cirrhosis.
Chlordiazepoxide, clonazepam, diazepamExtensively metabolized. Reduced clearance and prolonged half-life. Avoid use if possible.
BuspironeExtensively metabolized. Half-life may be prolonged. Reduce dosage and frequency in mild to moderate cirrhosis. Do not use in patients with severe HI.
Valproate Extensively metabolized; reduced clearance and increased half-life. Reduce dosage; monitor liver function tests frequently, especially in first 6 months of therapy. Avoid in severe HI if possible.
Lamotrigine Initial, escalation, and maintenance dosages should be reduced by 50% in moderate HI (Child-Pugh B) and by 75% in severe HI (Child-Pugh C).

 

Hepatotoxic Potential has been documented with the following medications:

  • Divalproex
  • Carbamazepine
  • Duloxetine
  • Naltrexone
  • Disulfiram
  • Nefazodone
  • Monoamine Oxidase Inhibitors (MAOIs)

Elevated Transaminases (AST, ALT) seen with

  • Olanzapine
  • Quetiapine
  • Carbamazepine
  • Divalproex
  • TCAs
  • SNRIs
  • Benzodiazepines
  • NSAIDs
  • Acetaminophen
  • Statins
  • ACEIs
  • Omeprazole
  • Allopurinol
  • Oral Contraceptives

Benzodiazepines and Liver Impairment

Benzodiazepines are usually avoided in patients with encephalopathy, but when needed (e.g., delirium tremens) use benzodiazepines that bypass phase I metabolism such as Lorazepam, Oxazepam, and Temazepam. These agents primarily undergo glucuronidation and are preferred in patients with hepatic insufficiency. 

Psychopharmacology in Cardiovascular Disease

  • Depression is common after myocardial infarction and in patients with cardiovascular disease.
  • Always rule out medical causes (e.g., medications, arrhythmia) of psychiatric symptoms in patients with cardiovascular disease.
  • Anti-platelet effect of SSRIs in ischemic heart disease may be helpful but it is unclear if this is clinically significant

Neuropsychiatric Side Effects of Cardiac Medications

MedicationNeuropsychiatric Effects
alpha-blockersDepression, Sexual Dysfunction
AmiodaroneHypothyroidism (depressed mood, fatigue)
ACEIsMood changes (rare)
Antiarrhythmics (especially lidocaine)Hallucinations, confusion, delirium
Beta-BlockersFatigue, Sexual Dysfunction
DigoxinVisual Hallucinations (colored rings or halos around objects), delirium, depression
DiureticsAnorexia, weakness, apathy (usually from electrolyte derangement), thiazides may cause erectile dysfunction

Pharmacokinetic Changes in Cardiac Disease

ConditionPharmacokinetic Changes
Right-Sided Heart FailureHepatic congestion and gut wall edema cause decreased absorption of medications.

Hepatic cirrhosis from chronic congestion can lead to reduced albumin production, ascites, increased alpha1-acid glycoprotein which will all cause changes in free drug levels and/or distribution of drugs
Left-Sided Heart FailureDecreased hepatic artery blood flow results in decreased Phase I.

Decreased renal artery blood flow from L sided heart failure leads to decreased GFR and renal dysfunction. This will decrease elimination of drugs primarily excreted through kidneys (e.g. lithium, pregabalin, gabapentin, paliperidone, memantine).

Antidepressants in Cardiovascular Disease

  • Sertraline (Zoloft): SAD HEART trial, ENRICHED trial
  • Mirtazapine (Remeron): MIND-IT Trials
  • Citalopram (Celexa): CREATE trial
  • Escitalopram (Lexapro): EsDEPACS trial (Kim et al. 2015)
  • Nortriptyline (50-150ng/mL): Relatively well tolerated in patients with impaired left ventricular dysfunction (Roose and Glassman 1989); TCAs have Type 1A (quinidine like) properties; TCA Users had increased risk of incident MI (Cohen 2000)
  • Paroxetine: Limited data suggesting preferential role in congestive heart failure
  • TCAs, Trazodone, and Mirtazapine (antihistamine properties) may increase appetite, promote weight gain, and help insomnia in patients with cardiac cachexia
  • Bupropion for weight loss or smoking cessation
  • Coronary Artery Disease: Escitalopram, Citalopram, and Sertraline are first line
  • Heart Failure: Consider Paroxetine, Mirtazapine, Bupropion, Venlafaxine, or Duloxetine (monitor blood pressure)

Q-T Prolongation Risk

The QT interval is found on standard electrocardiograms (ECG or EKG) and represents the interval measured from the onset of ventricular depolarization (onset of QRS complex) to the end of ventricular repolarization (end of the T wave). It is important to note that ventricular depolarization and repolarization are occurring simultaneously during the QT interval.

Antipsychotics

HIGH RISKMODERATE RISKLOW RISK
ThioridazineFluphenazineAripiprazole
ZiprasidoneHaloperidol* PaliperidoneLurasidone
IloperidoneRisperidone
Asenapine
Olanzapine**
Quetiapine
Clozapine
*All formulations of haloperidol, including IV, have similar effect on QT as most atypicals
**Recent review showed that IM Olanzapine has slightly less QT prolongation than IM Haloperidol
Generally, the typical antipsychotics are worse than atypicals (Phenothiazines are the worst offenders)

Antidepressants | Stimulants | Mood Stabilizers | Misc

MEDICATION COMMENTS
Citalopram (Celexa) Dose Dependent; Usually 10ms-20ms increase in QTc; Risk increases over 40mg/day; No studies have shown a link to TdP and sudden cardiac death
Escitalopram (Lexapro)Dose Dependent; Increases QTc by average of 7ms
Sertraline (Zoloft)Safest! Minimal QTc prolongation; Has never been associated with QTc prolongation
Venlafaxine (Effexor)Low risk of QTc prolongation (except in overdose)
Duloxetine (Cymbalta)Not associated with QTc prolongation
Mirtazapine (Remeron)Not associated with QTc Prolongation
Bupropion (Wellbutrin)Not associated with QTc Prolongation
Trazodone (Desyrel)Minimal/Mild QTc Prolongation (Overdose only)
Amitriptyline (Elavil), MaprotilineSignificant Risk of QTc Prolongation
ClomipramineLowest Risk of QTc Prolongation among TCAs
NOTE: Tricyclic Antidepressants prolong QT interval by multiple mechanisms including 1) Sodium channel blockade (widens QRS Interval); 2) Calcium channel blockade; 3) Ikr (potassium rectifier channel) blockade
Methylphenidate (Ritalin)Not associated with QTc Prolongation
Amphetamines (Adderall)Not associated with QTc Prolongation
Atomoxetine (Strattera)Unclear risk
Methadone, OxycodoneLinked to QTc prolongation and TdP
DonepezilCase Repots of QTc prolongation; Contraindicated in patients with bradycardia or heart block
Lithium>1.2 mmol/L in blood can prolong QTc
Valproic Acid, Lamotrigine, Carbamazepine, Oxcarbazepine, BenzodiazepinesMinimal to no risk of QTc Prolongation
Guanfacine, Clonidine, GabapentinMinimal to no risk of QTc Prolongation

Risk Factors for Torsades de Pointes (TdP)

  • Hypokalemia
  • History of prolonged QT
  • High doses
  • Multiple QT prolonging agents
  • Any history of cardiac disease
  • Female gender

Mood Stabilizers

  • Lithium: AV Block | Bradycardia | Avoid in Brugada syndrome
  • Valproic acid (Depakote): No direct cardiac effects | Thrombocytopenia (↑bleeding risk especially when prescribed in patients taking warfarin)

Anxiolytics

  • Use Lorazepam, oxazepam, temazepam (No phase 1)
  • Benzodiazepines alone have minimal effects on heart rate and blood pressure
  • Uncertain how benzodiazepines affect the autonomic nervous system
  • Buspirone has no cardiovascular effects

Psychopharmacology in Renal Disease

  • Caution with renally excreted drugs such as lithium, gabapentin, pregabalin, topiramate, paliperidone, risperidone, paroxetine, desvenlafaxine, venlafaxine, and memantine in ESRD
  • Edema is often present in ESRD and increases the volume of distribution for hydrophilic drugs
  • Uremic products circulating in ESRD may displace protein-bound drugs and cause toxicity (TIP: always try to get free drug levels when monitoring as total drug levels can be misleading)
  • Chronic renal disease can significantly modify phase 1 and 2 hepatic metabolism (e.g., reduction in P450 2C9, 2C19, 2D6, 3A4 metabolism).
  • Do not overlook potential impairment in renal metabolism as well (drugs are metabolized in the kidney as well as liver).
  • In general, in patients with renal insufficiency, use the rule of “two-thirds” (use medications at about 2/3 the normal dose)
  • Electrolyte disturbances in renal failure or diuretic therapy may increase the risk of cardiac arrhythmias especially in patients receiving medications that prolong the QTc interval. 

Psychiatric Symptoms in Patients with Renal Disease

  • Depression is the most common psychiatric disorder (20%-30%) in patients with chronic renal disease or end stage renal disease (ESRD)
  • Systematic review of symptoms in patients with ESRD revealed the following common symptoms: fatigue, pruritus, constipation, anorexia, Pain, sleep disturbance, nausea
  • Anxiety occurs in about half (50%) of patients with ESRD (e.g., phobia from needles, concerns about hemodialysis)
  • Posttraumatic Stress Disorder (PTSD) symptoms occurs in about 17% of patients with ESRD (mostly related to hemodialysis)
  • Delirium, psychosis, and cognitive dysfunction often accompany acute renal failure with uremia
  • Acute onset of renal failure accompanied by hallucinations should raise suspicion for toxic exposure (e.g., poisonous mushrooms, insecticides)
  • Psychotic symptoms in patients with ESRD may be due to primary psychosis, electrolyte disturbance, stroke, dementia, or toxicity from renal excreted drugs (e.g., acyclovir)
  • Uremia presents variably depending on the extent and rapidity of renal dysfunction
  • In patients with mild or chronic uremia, there is usually mild cognitive impairment, headache, fatigue
  • Untreated uremia progresses to lethargy, hypoactive delirium (mimics depression), and coma
  • Insomnia affects 50%-80% of dialysis patients (usually associated with metabolic changes, lifestyle factors, depression, and anxiety)
  • Restless leg syndrome (RLS) especially common in patients on hemodialysis and peritoneal dialysis (Note: Antidepressants and antipsychotics increase risk of RLS in ESRD)
  • Many renal/urological medications can cause psychiatric adverse effects such as anxiety, cognitive impairment, fatigue, confusion, insomnia, decreased libido, and irritability

Psychogenic Polydipsia 

  • Occurs in 6%-20% of psychiatric patients (most commonly in schizophrenia)
  • Drinking too much free water may lead to low plasma sodium levels (hyponatremia), especially if there is co-occurring syndrome of inappropriate ADH (SIADH) or other problems with water excretion
  • Diabetes insipidus is distinguished from psychogenic polydipsia by restricting a patient's water intake and measuring their urine osmolality (in Psychogenic Polydipsia, water restriction leads to urine that is more concentrated)
  • Treatment of Psychogenic Polydipsia*: Water restriction, clozapine, risperidone, olanzapine, B-blockers, acetazolamide, clonidine, enalapril, vasopressin antagonists (vaptans)
  • *Mostly from case studies, case series, and small RCTs

Hemodialysis (HD) Patients 

  • Duloxetine is not properly excreted in hemodialysis so be careful as toxicity can occur
  • Mirtazapine and Amitriptyline levels decrease after hemodialysis
  • Fluoxetine (and norfluoxetine) levels not affected by hemodialysis
  • Tricyclic antidepressants usually have a longer elimination half-life in hemodialysis patients
  • Lithium can be safely used in patients on hemodialysis. (Give the lithium dose after hemodialysis treatment)
  • Be careful with medications prone to causing orthostasis as patients on hemodialysis have rapid fluid shifts and are very susceptible to orthostatic hypotension

Dialyzable drugs (Conventional hemodialysis)

  • Gabapentin
  • Lithium
  • Pregabalin
  • Topiramate
  • Valproate

Dialyzable drugs (Peritoneal dialysis)

  • Lithium

Medications and Effects on Genitourinary System

MedicationEffect on GU/Kidneys
LithiumInterstitial nephropathy
Polyuria
TCAs & AnticholinergicsUrinary retention
Urinary hesitancy
Antipsychotics SIADH
Topiramate Renal Stones
Acidosis
SSRI/SNRIsSIADH
*SIADH, Syndrome of Inappropriate ADH

Depression

  • All antidepressants may be used in patients with renal failure
  • As a general rule, start low and go slow
  • Caution with renally excreted antidepressants in ESRD. These include lithium, paroxetine, desvenlafaxine, and venlafaxine*
  • Patients with ESRD are more sensitive to side effects of tricyclic antidepressants (TCAs). Nortriptyline and desipramine preferred over other TCAs
  • *Note that Venlafaxine half-life is prolonged in renal insufficiency and its clearance is reduced by more than 50% in patients undergoing dialysis
  • **Note that a large retrospective study found no increased adverse effects of higher versus lower doses of paroxetine, mirtazapine, and venlafaxine

Psychosis

  • All antipsychotics may be used in patients with renal failure
  • Caution with paliperidone as clearance is reduced in all degrees of renal impairment
  • Try to avoid agents prone to cause hyperglycemia in patients with ESRD and diabetes (e.g., Olanzapine, Clozapine)
  • In patients with electrolyte disturbances and rapid changes in fluid status, use agents least likely to prolong QT

Mood Stabilization

  • Lithium is entirely excreted by the kidneys; Contraindicated in acute renal failure BUT NOT CHRONIC RENAL DISEASE
  • For patients on dialysis, lithium is completely dialyzed and may be given as a single oral dose (300-600mg) following HD treatment
  • Check Lithium levels at least 2-3 hours after HD treatment because lithium is stored in tissues and needs time to re-equilibrate
  • For patients on peritoneal dialysis, lithium can be given in the dialysate
  • Careful with Lithium in patients with electrolyte disturbances as Lithium can prolong QT
  • Dose adjustment recommendations based on creatinine clearance are available for gabapentin, lithium, topiramate, and carbamazepine (Jacobson 2002).

Psychopharmacology in Neurological Diseases

Evidence-Based Options

Post Stroke Depression

  • SSRIs (Citalopram, Sertraline)
  • Stimulants (dextroamphetamines, methylphenidate)
  • Nortriptyline
  • Mood stabilizers (valproic acid)

Pseudobulbar Affect

  • Citalopram
  • Sertraline
  • Nuedexta

Parkinson’s Disease

Depression:

  • SSRIs
  • Donepezil
  • Rivastigmine
  • Pramipexole
  • TCAs
  • Duloxetine
  • Mirtazapine
  • Melatonin (for insomnia)
  • Pimavanserin (Nuplazid)
  • Bupropion
  • Psychostimulants (Low dose methylphenidate; Modafinil)

Psychosis:   

  • Reduce DA agonists▪Lower L-Dopa dose    
  • Reduce/discontinue anticholinergics
  • Donepezil
  • Rivastigmine    
  • Clozapine (low dose)
  • Quetiapine
  • Pimavanserin

Huntington’s Disease

Psychosis | Agitation | Chorea | Tics:

  • Haloperidol (low dose)
  • Atypical Antipsychotics (clozapine, quetiapine)
  • Tetrabenazine
  • Benztropine or other anticholinergic medications

Traumatic Brain Injury

Depression/Anxiety:

  • SSRIs (start low and go slow)
  • Nortriptyline

Post-Concussion Headache:

  • Amitriptyline
  • Nortriptyline 

Mania/Mood lability:

  • Valproic acid
  • Carbamazepine

Cognitive Enhancement**:

  • Stimulants (amphetamines, methylphenidate, modafinil)
  • Milnacipran
  • Amantadine

**Controversial results with SSRIs, Antipsychotics, Acetylcholinesterase inhibitors

Seizures

Antipsychotics and Seizure Risk  
High RiskIntermediate RiskLow Risk
Chlorpromazine (> 1000mg/day)Chlorpromazine (<1000mg/day)Aripiprazole
Clozapine (>300mg/day)Clozapine (<300mg/day)Fluphenazine
OlanzapineHaloperidol
QuetiapineMolindone
ThioridazinePimozide
Risperidone
Ziprasidone
Estimate of seizure risk derived collecetively from clinical trials data, observational studies, and case reports

Child-Pugh Score Calculator

References

  1. Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
  2. S. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill (pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  3. Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
  4. McCarron, Robert M., et al. Lippincotts Primary Care Psychiatry: for Primary Care Clinicians and Trainees, Medical Specialists, Neurologists, Emergency Medical Professionals, Mental Health Providers, and Trainees. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th Ed.
  8. Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st Ed. 2012. APP.

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