Psychopharmacology and General Medical Conditions

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Psychopharmacology and General Medical Conditions

• David A Fohrman, M.D.

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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 lt 1
• C 60
• D 22
• E none of the above

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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

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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

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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

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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

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What happened?

• Pt became delirious due to unknown etiology
• Surgeon assumed delirium was an uncommon
  presentation of a common condition sepsis
• Based on the surgeons experience/cohort of
  patients that he or she normally saw
• Eventually correct diagnosis made of serotonergic
  syndrome

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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.

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Question

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

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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

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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?

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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.
  

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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)

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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

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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
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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.
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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)

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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

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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?

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Question

• Which of these is a psych symptom?
• I feel depressed
• I cant sleep
• I have chest pain
• I feel irritable
• I cant concentrate
• I get headaches all of the time
• I feel stressed out
• I have intermittent diarrhea and constipation

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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

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Answer 2

• Question
• What percent of the patients 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)

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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.

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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

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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 its use
• Emphasis on evaluating for psychopharmacological
  interactions (step 2)

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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
  patients psychiatric symptoms.
• Recommend keeping them in your desk drawer or
  where they are easily accessible

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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.

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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

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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

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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?
• Step5 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.

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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

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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

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Inclusion Criteria

• Medical condition must have specific psychiatric
  symptom (mania, depression, etc) as part of its
  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

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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)

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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

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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.

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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
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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)

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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

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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

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Drugs that may cause Psychiatric Symptoms

• Please see handout
• Drug
• Adverse reaction
• Psychosis
• Depression
• Mania
• Anxiety
• Adapted fromDrugs that may cause psychiatric
  symptoms The medical Letter, Vol. 44, July,
  2002. p.59-62

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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.

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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

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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)

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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

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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)

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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

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Inhibitor added to a substrate

• 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

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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.

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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

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Rational

• Ethinylestradiol is a 3A4 substrate and
  Oxcarbazepine is a 3A4 inducer, not at powerful
  as carbamazapine
• But can be clinically significant
• Consider double checking what other docs did/do

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Displacement

• 48 year old male with history of bipolar disorder
  was treated with divalproic sodium (Depakote),
  1250mg and Quetiapine (Seroquel), 500mg
• Sensation of tingling in arm, lower arm more then
  20 minutes
• Concern about a transient ischemic attack (TIA)
  given untreated hypertention (155/95) and family
  hx
• Started on enalapril 5mg bid and aspirin
  325mg/day
• Within 3 days, onset of fatigue, terrible fatigue
  and sedation and incoordination
• Prevention consistent with valproic acid toxicity
• Valproic acid level is unchanged 95ug/ml
• Recommendation d/c aspirin

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Rational

• Divalproic acid tightly bound to plasma proteins
• Aspirin is also tightly bound to proteins
• Displace valproic acid
• Only changed ratio of bound to unbound valproic
  acid
• Total amount of divalproic acid unchanged

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Excessive pharmacologic synergy

• 35 year old woman with panic disorder
• History of polysubstance dependence
• Taking celexa 40mg//day
• Imipramine (Tofranil), 150mg/day
• One winter contacted a common cold with nasal
  congestion, sinus pain
• Took diphenhydramine (Benadryl) 25mg tid
• Within three days, blurry vision, dry mouth,
  constipation
• Recommendation stop Benadryl

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Rational

• Excessive pharmacological synergy
• Imipramine is strongly anti-cholinergic compound
• Diphenhydramine is also anti-cholenergic
• Synergistic reaction

56
Conclusion

• GMC, pharmacology and psychiatric symptoms can
  have very complex interactions
• One way to approach this is to use systematic
  approaches that are evidence and triage based
• Consider getting/using updated p450 tables/
• Getting help from our pharmacists.

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Questions

• If you have any questions please contact me at
  307-778-7349
• Thank you for your time and attention.