Psychopharmacology In Medically Complex Patients

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 is a summary using the references at the bottom of this page.

Pharmacokinetics and Dosing in Liver Disease

  • Bioavailability (BA): proportion of drug delivered to systemic circulation
    • For orally administered drugs: BA is influenced by gut function and first pass metabolism
  • Small intestine is the major site of absorption for most orally administered drugs
  • Liver disease may cause gastroparesis or impaired GI motility (which delays drug delivery to intestine)
  • Vascular congestion (cirrhotic patients with portal hypertension) may slow absorption
  • Hepatic insufficiency associated with decreased first pass metabolism and hepatic biotransformation (CYP450 system) leading to increased plasma drug levels
  • Quantitative changes in plasma protein levels due to hepatic insufficiency alters protein binding and free drug levels (but likely clinically insignificant)
  • Ascites and peripheral edema increase volume of distribution of hydrophilic drugs leading to decreased plasma 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 or avoided
  • 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 TBW as paracentesis, diuresis, and fluid loss can cause rapid changes in fluid status

Adjust dose according to Child Pugh Score:

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

CHILD-PUGH SCORING

1 point

2 points

3 points

Albumin (g/dL)

>3.5

2.8-3.5

<2.8

Ascites

None

Mild

Moderate

Bilirubin (mg/dL)

<2.0

2-3

>3.0

Encephalopathy

None

Mild to Moderate (grade 1-2)

Severe (grade 3-4)

International Normalized Ratio

<1.7

1.7-2.3

>2.3

 

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).

Psychotropics with hepatotoxic potential:

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

 

Elevated Transaminases (ALT>AST) seen mostly with:

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

 

Liver Impairment & Alcohol Withdrawal use:

  • Benzodiazepines are usually avoided in patients with encephalopathy, but when needed (e.g., delirium tremens) use benzodiazepines that bypass phase I
  • The following benzodiazepines primary undergo glucuronidation and are preferred in patients with hepatic insufficiency (HI):
    • Lorazepam
    • Oxazepam
    • Temazepam

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.

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).

Anxiety/Anxiolytics/Sedative-Hypnotics

  • Use Lorazepam, oxazepam, temazepam (No phase 1)
  • Benzodiazepines alone have minimal effects on HR/BP
  • Uncertain how benzos effect autonomic nervous system
  • Buspirone has no cardiovascular effects

Depression/Antidepressants

  • Sertraline (Zoloft) – SAD HEART trial (efficacy limited to recurrent depression, depression before cardiac event, or severe depression with HAM-D >20; trend toward reduced adverse cardiac events); ENRICHED trial (reduced mortality, reduced adverse cardiac events)
  • 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
  • Coronary Artery Disease: Escitalopram, Citalopram, and Sertraline are first line
  • Heart Failure: Consider Paroxetine, Mirtazapine, Bupropion, Venlafaxine, or Duloxetine (monitor blood pressure)
  • 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
  • Anti-platelet effect of SSRIs in ischemic Heart disease may be helpful but unknown if clinically significant

 

Psychosis/Antipsychotics:

QTc prolongation Risk

 

Risk Factors for Torsades de pointes:

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

 

Mood Stabilization:

  • 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)

Psychopharmacology in Renal Disease

  • Psychiatric Symptoms in Patients with Renal Disease
    • Depression most common disorder (20%-30%)
    • Systematic review of symptoms in patients with ESRD: fatigue 71%, pruritus 55%, constipation 53%, anorexia 49%, Pain 47%, sleep disturbance 44%, nausea 33%
    • Anxiety in about 50% of ESRD pts (phobia from needles, hemodialysis); PTSD symptoms in 17% of ESRD pts in one study 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 pts with ESRD may be due to primary psychosis, electrolyte disturbance, stroke, dementia, or toxicity of renal excreted drugs (acyclovir)
    • Uremia presents variably depending on extent and rapidity of renal dysfunction. Mild or chronic uremia: usually mild cog impairment, headache, fatigue
    • Untreated uremia progresses to lethargy, hypoactive delirium, and coma
    • Insomnia affects 50%-80% of dialysis patients (usually associated with metabolic changes, lifestyle factors, depression, and anxiety)
    • Restless leg syndrome especially common in pts on hemodialysis and peritoneal dialysis. Antidepressants and antipsychotics increase risk of RLS in ESRD.
    • Many renal/urological medications can cause psychiatric adverse effects (anxiety, cog impairment, fatigue, confusion, insomnia, decreased libido, irritability)

Psychogenic polydipsia (PP):

  • Occurs in 6%-20% of psychiatric patients (most commonly in schizophrenia)
  • Resulting hyponatremia is usually mild and asymptomatic unless co-occurring with SIADH or other problem with water excretion
  • Diabetes insipidus is distinguished from psychogenic polydipsia by water restriction and measuring urine osmolality. In PP, water restriction leads to urine that is more concentrated
  • Treatment of PP*: Water restriction, clozapine, risperidone, olanzapine, B-blockers, acetazolamide, clonidine, enalapril, vasopressin antagonists (vaptans)

*Mostly from case studies, case series, and small RCTs

Pharmacokinetics/Pharmacodynamics in Renal Disease

  • Caution with renally excreted drugs in ESRD (lithium, gabapentin, pregabalin, topiramate, paliperidone, risperidone, paroxetine, desvenlafaxine, venlafaxine, memantine)
  • Edema is often present in ESRD, increasing volume of distribution for hydrophilic drugs
  • Uremic products circulating in ESRD may displace protein bound drugs! 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 (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” (2/3 the normal dose)
  • Electrolyte disturbances in renal failure or diuretic therapy may increase the risk of cardiac arrhythmias especially in pts receiving QT prolonging agents

Hemodialysis (HD) Patients:

  • Up to 70% of patient older than 55 have moderate to severe chronic cog impairment
  • Duloxetine is not properly excreted in HD (CNS Toxic)
  • Mirtazapine and Amitriptyline levels ↓ after HD
  • Fluoxetine (and norfluoxetine) levels not affected
  • TCAs have longer elimination half-life in HD pts
  • Lithium in HD patients (give dose after HD treatment)
  • Be careful with medications prone to cause orthostasis as HD patients have rapid fluid shifts and are very susceptible to orthostatic hypotension
  • Dialyzable drugs (Conventional HD): Gabapentin, Lithium, Pregabalin, Topiramate, Valproate
  • Dialyzable drugs (Peritoneal dialysis): Lithium

Medications and effects on Genitourinary (GU) system:

Medication

Effect on GU/Kidneys

Lithium

Interstitial nephropathy, Polyuria, Nephrogenic diabetes insipidus, hypernatremia

TCAs & Anticholinergics

Urinary retention, Urinary hesitancy, SIADH, hyponatremia, psychogenic polydipsia  

Antipsychotics

SIADH

Carbamazepine & Oxcarbazepine

SIADH, psychogenic polydipsia, hyponatremia

Topiramate

Renal Stones, Acidosis

SSRI/SNRIs

Duloxetine

SIADH, psychogenic polydipsia, sexual dysfunction, hyponatremia

Urinary retention

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 (lithium, paroxetine, desvenlafaxine, venlafaxine*)
  • Patients with ESRD more sensitive to side effects of 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 Rheumatology Disorders

Rheumatoid Arthritis and Depression:

  • Sertraline (little side effects up to 100mg/day)
  • Dothiepin (Effective and well tolerated for depression and anxiety)
  • Doxepin (some data)
  • Paroxetine (20-40mg/d) and Amitriptyline (75mg-150mg/d): Similar efficacy for pain/depression but paroxetine better tolerated

Osteoarthritis and Depression

  • Duloxetine effective in elderly patients with osteoarthritis
  • Antidepressants reduce depression and then reduce pain and disability

Pain

  • Low dose TCAs (amitriptyline 25mg/day)
  • Duloxetine 60-120mg/day

Lupus Cerebritis

  • No RCTs
  • Corticosteroids first line for CNS inflammation
  • Antipsychotics with high D2 receptor potency generally more effective in severe cases for controlling symptoms while on corticosteroids
  • Monitor closely for EPS and seizures
  • Anticonvulsant mood stabilizers often used for prophylaxis or treatment of seizures as well as mood stabilization
  • Avoid benzodiazepines

Drug Induced Lupus (DIL)

  • Presentation of DIL: Usually no CNS involvement, mild cytopenia, elevated ESR, elevated antinuclear antibody titers, Antihistone antibodies positive in up to 95% of patient but are not pathognomonic of DIL
  • Chlorpromazine and carbamazepine low risk
  • Valproic acid, other anticonvulsants, phenelzine, and lithium very low risk
  • Isolated reports with sertraline and bupropion
  • More commonly caused by rheumatological drugs (infliximab and adalimumab) than psychotropics
  • After discontinuing drug, symptoms and titers decline over weeks but recovery can take more than a year

Psychiatric Side Effects of Medications used in treating Rheumatology Disorders

Medication

Psychiatric Side Effects

Azathioprine

Delirium

Corticosteroids

Mood lability, euphoria, irritability, anxiety, insomnia, mania, depression, psychosis, delirium, cognitive disturbance

Cyclophosphamide

Delirium (at high doses)

Cyclosporine

Anxiety, delirium, visual hallucinations

Hydroxychloroquine

Confusion, psychosis, mania, depression, nightmares, anxiety, aggression, delirium

Immunoglobulin (IV)

Delirium, agitation

Leflunomide

Anxiety

Methotrexate

Delirium (at high doses)

Mycophenolate mofetil

Anxiety, depression, sedation (all rare)

NSAIDs (high dose)

Depression, anxiety, paranoia, hallucinations, concentration, hostility, confusion, delirium

Sulfasalazine

Insomnia, depression, hallucinations

Tacrolimus

Anxiety, delirium, insomnia, restlessness

Psychopharmacology in Respiratory Disease

Respiratory depression is commonly seen with:

  •   Anticholinergics
  •   Benzodiazepines
  •   Barbiturates

 

Evidence for efficacy and safety exists for:

  • Citalopram
  • Sertraline
  • Paroxetine
  • Nortriptyline
  • Desipramine
  • Buspirone
  • Modafanil
  • Atomoxetine
  • Zolpidem
  • Zopiclone
  • Melatonin
  • Ramelteon

Try to avoid the following medications in patients with respiratory diseases:

  • Obstructive Sleep Apnea (OSA): Mirtazapine, TCAs, Benzodiazepines
  • Asthma/COPD: Highly anticholinergic antipsychotics, beta blockers

Carbamazepine has elevated risk of diffuse parenchymal lung disease

Psychopharmacology in Patients with Neurological Disease

 

Post Stroke Depression:

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

Pseudobulbar Affect:

  • Citalopram
  • Sertraline
  • Nuedexta

Parkinson’s Disease

Depression:

  • Pramipexole
  • SSRIs
  • TCAs
  • Duloxetine
  • Pimavanserin? (case studies)

Psychosis (order of what to do):

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

 

Huntington’s Disease

Psychosis/Agitation/Chorea/Tics:

  • Haloperidol (low dose)
  • Atypical Antipsychotics (clozapine, quetiapine)

Traumatic Brain Injury (click here)

Antipsychotics and Seizure Risk

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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