Psychopharmacology and General Medical Conditions

1. Psychopharmacology and General Medical Conditions David A Fohrman, M.D.

2. Question What percent of your patients with psychiatric complaints have a General Medical Condition (GMC)/and or drug interaction that is causing or exacerbating his or her symptoms? A: 30% B: < 1% C: 60% D: 22% E: none of the above

3. Overview • Relationship between Psychopharmacology, General Medical Conditions and Psychiatric diagnosis • Algorithm for the evaluation of patients presenting with specific psychiatric symptoms • Psychopharmacological interactions leading to psychiatric problems. • Note: Talk focuses on pediatric patients but generalizable to adults

4. Psychopharmacology, GMC and Psychiatry • Complex relationship between psychopharmacology, GMC and psychopharmacology • Multiple layers of interactions, including biological, environmental and system issues • All the more challenging because etiology of psychiatric conditions mostly unknown • DSM diagnosis based on statistical symptom clusters • The following is a case example to introduce this topic

5. Case Report • 45 year old woman presented with recurrent major depression and a family hx of opioid dependence • Taking (Paxil) 20mg/day with efficacy • While skiing, she suffered a left humeral fracture. • Started on tramadol (Ultram) 75mg po q 4 for pain not to exceed 400mg per day • Did no use narcotics because of concerns about getting ‘hooked’ • Experienced only partial relief from pain • Four days experienced onset of flushing, diarrhea, muscle twitching, sedation, fevers, confusion as to time and place

6. Case report, continued • Surgeon suspected infection • Began work up • While waiting results, Pt had a grand mal seizure • Transferred to ICU • Subsequently considered other potential etiologies • d/c Tramadol and Paxoetine, started on morphine • Symptoms resolved

7. What happened? • Pt became delirious due to unknown etiology • Surgeon assumed delirium was an uncommon presentation of a common condition; sepsis • Based on the surgeon’s experience/cohort of patients that he or she normally saw • Eventually correct diagnosis made of serotonergic syndrome

8. Serotonergic syndrome • Due to excessive stimulation of 5HT receptors centrally and peripherally • Symptoms; diarrhea, flushing, tachycardia, syncope, delirium, seizure, (can be fatal) • Case: • Interaction between Ultram and Paxil • Paxil inhibits p450 2D6 metabolism • Tramdol is a substrate of 2D6 and blocks serotonergic re-uptake (on post synaptic 5HT receptors) and lowers seizure threshold.

9. Question: • Could this diagnosis/ appropriate treatment have been made faster? • Perhaps, if etiology of delirium was addressed systematically

10. Mnemonic to identify potential etiologies of delirium • I- Infectious : Encephalitis, meningitis, syphilis, HIV • W- Withdrawal : Alcohol, barbiturates, sedative-hypnotics, benzodiazepines • A- Acute metabolic : Acidosis, alkalosis, electrolyte disturbance, hepatic or renal failure, dialysis, porphyria • T -Trauma : Heat stroke, postoperative, bums, head injury • C- CNS pathology/psychopathology : Abscess, hemorrhage, hydrocephalus, multiple sclerosis, seizures, stroke, tumors, Wilson's disease, • H- Hypoxia : Anemia, carbon monoxide, hypotension, cardiac failure, pulmonary emboli/failure • D- Deficiencies : B12, folate, niacin, thiamine • E- Endocrinopathies : Hyper(hypo)adrenal corticism, hyper(hypo)glycemia, hyper(hypo)thyroidism, hyper(hypo)parathyroidism • A- Acute vascular : Hypertensive encephalopathy, shock, vasculitis • T- Toxins/drugs : Medication, pesticides, solvents • H- Heavy metals : Arsenic, lead, manganese, mercury, thallium “I WATCH DEATH”

11. Challenge • Can we systematically evaluate patients with (or without) a prior psych diagnosis with new onset mental health related symptoms for pharmacological and non psychiatric (General medical Conditions) that could be causing this/these symptoms? • Given the our time, economic and knowledge constraints?

12. Significance of the Problem • Many adults have undiagnosed GMC contributing to their psychiatric complaints. • Since 1937 more then 40 studies (mostly in adults) in psychiatric inpatient and outpatient settings • Undiagnosed medical conditions vary between 20% and 60% • (Koranyi, 1972; Hall,1980,1981; Davies, 1965) • Lower rates for studies that exclude patients with co-morbid somatic symptoms (Korn, 2000) • Of note, several studies found the incidence of GMC causing psychiatric complaints to be rare • These studies used strict criteria for causality.

13. Psychiatrists may minimize their role in identifying medical causes of psychiatric symptoms • Non psychiatric physicians are responsible for identifying and treating most medical conditions • Psychiatrist may lump all pediatric medical conditions together • Co-morbid conditions NOT causing psychiatric illness • Co-morbid conditions exacerbating/causing symptoms. • Only 2-4% of Psychiatrists perform a physical exam on a outpatient basis (McIntyre and Romano, 1979)

14. “Medical Clearance” of patients with primary psychiatric diagnosis • Assessment guidelines minimize the importance of possible medical* causes of psychiatric symptoms • DSM (Appendix A) algorithms use yes/no questions to include or exclude substance induced or general medical conditions • American Academy of Pediatrics: Guidelines for the evaluation and treatment of Attention Deficit Disorder: • ‘assumes an uncomplicated case of attention deficit hyperactivity disorder’ (p.3) *medical causes refer to pharmacological, substance induced, general medical, genetic and neurodevelopmental causes of psychiatric symptoms

15. Some medical disorders are much more common in psychiatric patients then in the general pediatric population • Porphyria 0.21% incidence in psychiatric inpatients (Tishler et al, 1985) • Abdominal pain usually 1st sign of attack; Precedes neurologic deficit • Neuropathy, Seizures • Tendon reflexes: Reduced • Autonomic: Sympathetic & Parasympathetic involvement • Mental status changes: Psychosis; depression; Dementia Urine of patient with Acute intermittent Porphyria: often changes color when exposed to sunlight

16. Some medical disorders are much more common in psychiatric patients then in the general pediatric population (example #2) • Velocardiofacial Syndrome 6.4% in early onset Schizophrenia; 0.025% in general population (Usiskin, 1999) • Symptoms: midline facial abnormalities; cleft palate, heart abnormalities, learning disabilities, psychosis Child 8 years old with VCFS, note: broadening upper portion of his nose.

17. Some medical disorders are much more common in psychiatric patients then in the general pediatric population • Rare pediatric medical conditions may be significantly more common in psychiatric patients because of the medications they are taking • Folate Deficiency and patients with Bipolar Disorder taking anticonvulsant medications (Morris, 1995,2003) • Psychosis in patient with Tuberculosis; side effect of Isoniazid (Alao et al, 1998)

18. Systemic factors make effective diagnosis of underlying medical conditions difficult • Limited Time • Mental illness may magnify or minimize patient pain thresholds • decreased with depression, anxiety, • increased with schizophrenia (Asmundson, 1999; Kudoh, 2000) • Patients (and/or family members) with mental illness may be poor historians

19. Tables of GMC causing psychiatric conditions are not evidence based. • Tables based one or two authors • Lewis Textbook tables are from Concise Guide to Consultation Psychiatry, Wise et al (1988) • Textbook of Consultation-Liaison Psychiatry (based on clinical opinion (1996) • no prevalence or incidence data • Tables are also NOT prioritized by frequency/rate • No algorithm/ triage approach for diagnosing • ? When would you look for an uncommon condition • Which medical condition would you evaluate for?

20. Question: • Which of these is a psych symptom? • ‘I feel depressed’ • ‘I can’t sleep” • ‘I have chest pain’ • ‘I feel irritable’ • I can’t concentrate • I get headaches all of the time • I feel stressed out • I have intermittent diarrhea and constipation

21. Answer: • It depends • On age, demographics of patient. • Chest pain in a 18 year old with a prior cardiac history is very different then chest pain in an 80 year old. • On the setting where you are asking the question • Your office, ER, on the phone • Acute vs. chronic problem • On how information is presented • Straightforward, with lots of effect • On associated symptoms, somatic, emotional, interpersonal • Temporal Context • New medication, environmental exposure

22. Answer #2 • Question: • What percent of the patient’s you are seeing with a new onset psychiatric complaint have a medical condition/and or drug interaction that is causing his or her symptom? • Answer: • E: none of the above • (extremely difficult to determine true incidence/prevalence)

23. Prevalence of Mental Illness due to a medical conditions in Pediatrics • Incidence/prevalence is location dependent • i.e. a patient takes a corticosteroid and becomes clinically manic • A psychiatrist will diagnosis as ‘substance induced mania’ • An mental health provider would most likely call this an ‘adverse drug reaction’. • Once a diagnosis is made, physicians may stop looking for other possible etiologies for that patients symptoms • Problem compounded by diagnostic nomenclature • Diagnosis are make in psychiatry phenomenologicaly • Countertransferance • Your (usually negative) emotional reaction to certain patients.

24. Recommendation: • Systematically evaluate (and re-evaluation) for medical conditions that may be causing or exacerbating psychiatric symptoms in your patient with new onset or change in symptoms consistent with a psychiatric diagnosis • Helps avoid all or none (dichotomous) thinking • Minimize provider bias • ‘Pick your provider, pick your diagnosis’ • With a headache, a neurosurgeon will send you for an MRI, primary care – probably not, psychiatrist, almost never

25. Recommendation continued • Use an algorithm to evaluate specific symptoms: depression, mania, sustained attention, psychosis and anxiety • Intent is to give you a means to systematically evaluate these patients. • Only presenting an overview of it’s use • Emphasis on evaluating for psychopharmacological interactions (step #2)

26. Algorithms for assessment of medical causes of psychiatric symptoms • Mental mnemonic to identify medical causes of psychiatric symptoms • less then a minute to use • Systematically identify the following medical conditions: substances of abuse, pharmacological agents, general medical conditions, neurodevelopmental conditions and learning disabilities, • Identify other objective symptoms (such as weight loss or irritability) that may be exacerbating a patient’s psychiatric symptoms. • Recommend keeping them in your desk drawer or where they are easily accessible

27. Algorithms for assessment of medical causes of psychiatric symptoms • Created for children, but also applies for adults • Four symptoms: • Depression • Psychosis, • Attention deficit • mania • Triage model: initially only evaluate for “common” medical conditions in the present of unexplained somatic symptoms. • Can help re-assure patients (and/or their parents ) that everything (reasonable) is being done to work up potentially treatable causes of their psychiatric symptoms. • Previously did focused nuerological exams on all of my patients.

28. Identification of medical conditions causing mental illness in pediatric patients. • Create Database to collect case reports; Antidote for the Anecdote (Wise, 1988) • Guerrero (2003) proposed a 12 step approach to general medical evaluation for child and adolescents who present in the emergency room. • Create evidence based tables of medical conditions that may present with prominent psychiatric symptoms

29. Algorithms • Example Depression (most complicated algorithm) • Eight (9) steps • First get history related to clinically signficant depressive disorder • Step #1: Is patient taking substances that may be exacerbating these symptoms? • Yes/no • Step #2: Is child (adult) taking medications that may be exacerbating their psychiatric symptoms. • Yes/no

30. Algorithm for depression continued • Step #3: Does the patient have a known medical condition, including untreated pain, that could be causing or exacerbating their symptoms • Step #4: Does the patient have unexplained somatic symptoms suggestive of an undiagnosed GMC? • Step#5: If considering a diagnosis MDD or Dysthymia, are specific neurovegative symptoms in excess of what would expect for that diagnosis? • Step #6: Is patient functioning significantly below age expected norms • More for children, but something to consider for adults as well • Step #7: Is patient signficant psychomotor slowed or show signs of a psychotic depression? • Step #8: Does patient have an atypical presentation and/or is treatment resistant? • Consider rare GMC that can cause depressive symptoms.

31. Tables of Pediatric medical conditions with prominent psychiatric symptoms • Partial list of sources: • Consult-Liaison Textbooks: Rundell and Weiss • Neuropsychiatry Textbooks: Adult, Pediatric • Review articles: ADHD (Pearl, 2001), Bipolar disorder (Krishan, 2005; Heila, 1995)) • Pubmed Search: Mesh Terms: organic mood disorder, organic anxiety disorder, with child or adolescent; challenge • Review 1980-2004 Psychosomatic, American Journal of Child and Adolescent Psychiatry for case reports and review articles

32. Evidence based tables of differential diagnosis of medical conditions that may cause or exacerbate psychiatric illnesses. • Advantages: • Earlier diagnosis of uncommon and rare GMC • Increased confidence psychiatric illness are truly ‘primary’ • Educational • Disadvantages • May be used to inappropriately order tests • Clinicians or patients/ families may focus too much on an exhaustive search for an elusive ‘organic etiology’ • Clinicians may view lists as ‘inclusive’ • Lists do NOT include patients prior GMC • Lists exclude conditions without sufficient evidence

33. Inclusion Criteria • Medical condition must have specific psychiatric symptom (mania, depression, etc) as part of it’s clinical presentation. • The specific psychiatric symptom resolve with treatment of the underlying medical condition OR • There is evidence that specific psychiatric symptoms occur at a rate significantly greater then what one would find in the general population. • Children over three years old

34. Overview of Tables • Four Tables of Medical Conditions that may cause or exacerbate psychiatric symptoms • Psychosis, • Poor Sustained Attention, • Mania • Depression • Tables do NOT include disorders seen only in patients with • mental retardation or • patients with a pre-existing medical condition (i.e. congenital hypothyroidism)

35. Relationship between mood disorders and medical differential diagnosis • Many psychiatric disorders consist of both internal and external symptoms. • Internal refer to symptoms such as depression, guilt, or suicidal ideation • External refer to symptoms such as such as sleep disturbance, weight loss, irritability and chronic fatigue • Non-psychiatric clinicians routinely consider the differential diagnosis of “external” symptoms as part their clinical practice

36. Medical conditions which may cause or exacerbate symptoms of DEPRESSION • Many medical conditions implicated, few have evidence to support a causal relationship • Polycystic Ovary Disease • associated with significant rates of depression (Rasgon et al, 2002) • Celiac Disease • Treatment in adolescents alleviates depressive symptoms (Pynnonen et al, 2005) • If there is a diagnosis of Major Depression or dysthymia consider if symptoms such as sleep disturbance, weight loss, fatigue, and poor concentration are the result of an co-morbid medical condition.

37. Medical conditions which may cause or exacerbate symptoms of Psychosis Most Medical conditions were one of six categories: Genetic Disease, Collagen Vascular Diseases, Endocrinology, Infectious Disease Neurology, or Toxicology Mercury Poisoning Symptoms: paresthesias, headaches, ataxia, dysarthria, visual field constriction Acrodynia: (painful extremities) pink discoloration of hands, feet

38. GMC which may cause or exacerbate symptoms of poor sustained attention • Well known associations between Absence Seizure Hearing/visual loss, Sleep disordered Breathing/ Obstructive sleep apnea, Sleep Disorder Breathing/ Obstructive Sleep Apnea, Tourette Disorder and ADD symptoms • The following medical conditions are less well known • Allergic rhinitis (Brawley et al, 2002, Wilken et al, 2002) • Anemia, with or without iron deficiency (Konofal et al, 2004; Sever et al, 1997) • Restless leg/periodic limb movements in sleep (Picchietti et al, 2004; Gaultney et al, 2005)

39. GMC that may cause or exacerbate symptoms of MANIA • Very few general medical conditions “cause” manic symptoms. • case reports: hyperthyroidism, head trauma, seizures, Cushing Disease • Most often, medical conditions exacerbate clinical symptoms of mania. • If there is a diagnosis of Pediatric bipolar disorder consider if the symptom of irritability is due to a co-morbid medical problem

40. Focus on pharmacological interaction that can exacerbate cause psychiatric symptoms • Remainder of talk will focus on pharmacological interactions • Direct medication adverse reactions • Drug-drug • Psychiatric- non psychiatric • Non-psychiatric- non psychiatric • Other

41. Drugs that may cause Psychiatric Symptoms • Please see handout • Drug • Adverse reaction: • Psychosis • Depression • Mania • Anxiety • Adapted from:“Drugs that may cause psychiatric symptoms” The medical Letter, Vol. 44, July, 2002. p.59-62

42. Examples of psychiatric side effects of GMC medications • A 48-year-old woman with temporal lobe epilepsy and no prior history of psychiatric illness was started on topiramate (TPM). • The dose titrated up to 150 mg twice daily over 14 weeks and led to a significant reduction in seizure frequency. • Upon reaching this dose, she developed intense pruritus • belief that her skin was infected by parasites. • She was diagnosed with delusional parasitosis • Her TPM was weaned off and her DP settled completely without the use of antipsychotic medication. • DP is characterized by the unshakeable conviction that small organisms infest the body despite the absence of confirmatory medical evidence.

43. NSAID induced psychotic symptoms • Psychosis, infrequently reported with NSAIDs, but should be suspected in an elderly patient started on a regimen of indomethacin who acutely develops disorientation, paranoia, or hallucinations. • Also possible problem post partum with use of indomethacin • The hospital records of patients experiencing any postpartum complication between 1994 and 1999 were reviewed for adverse drug reactions (ADR) attributed to indomethacin • 32 cases identified • symptoms were often severe and included dizziness, anxiety, fear, agitation, affective lability, depersonalization, paranoia, and hallucinations. • Possible mechanisms: • a postpartum dopamine super sensitivity exacerbated by prostaglandin inhibition • structural similarity between serotonin and indomethacin

44. Drug-Drug interactions • Core concepts • Lipophilic substances must be made hydrophilic to be excreted from the body • Phase one - P450 system – oxidative metabolism • Phase II – conjunction – UGTs (Uridine 5’-diphosphate glucuronosyltransferases) perform glucocuronidation (conjugations)

45. Patterns of Drug-Drug interactions • #1- inhibitor is added to a substrate (or visa versa) • Increases drug levels • Example: paroxeline is added to nortriptyline/( nortriptyline is added to paroxeline) • Paroxeline inhibits 2D6; nortryptyline is a 2D6 inhibitor • #2 An inducer is added to a substrate (or visa versa) • Example: carbamazapine is added to haloperidol (haloperidol is added to carbamazapine) • Carbamazapine is an inducer of 3A4, 1A2, and phase II gluconeration; haloperidol is a substrate for 3A4, 1A2, 2D6

46. Substrate induced to an inhibitor • 50 year old woman with hx of atypical depression • Controlled with fluoxetine (prozac) 40mg/day • Cholesterol 275mg/day • Started on atorvastatin (lipitor), titrated to 30mg/day. • Cholesteral still high, so dose increased to 50mg/day • After one month, developed fatigue, confusional state, extreme fatigue, elevation of LFTs, • d/c atorvastatin • Started simvastatin • Return of extreme fatigue mild confusion • d/c simvastatin • d/c proazac; started on celexa and pravastatin (Pravachol)

47. Rational • Atorvastatin and Simvastatin are strong metabolized by 3A4 • Fluoxetine strongly inhibits 2D6 • Metabolite – norfluoxetine inhibits 3A4 • Combination greatly, and progressively increased dose of atorvastatin and simvastatin

48. 31 year old woman with chronic paranoid shizophrenia Treated with olanazapine (zyprexa) 20mg/day Developed symptoms of flank pain, fevers Diagnosis of pyelonephritis Started on ciprofloxacin, 500mg bid for 7 days By day 4, pt with inceased stiffness, increased sedation, postural tremor and constipation Decrease dose of olanazapine to 10mg until finish dose of ciprofloxacin Inhibitor added to a substrate

49. Rational • Olanazapine is a 1A2 substrate, also 2D6, phase II gluconeration • Ciprofloxacin is a potentat inhibitor of 1A2 • Lead to an increase in the level of Olanazapine • Side effects • Decreasing dose reversed this effect.

50. Substrate added to an Inducer • 35 year old married women with a seizure disorder remained seizure free while taking tegretol • Switched to Trileptal because wanted to use BCPs containing ethinylestradoil • With in one year was pregnant