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REVIEW OF PSYCHIATRY Geriatrics.ppt

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REVIEW OF PSYCHIATRY Geriatrics.ppt Powered By Docstoc
					Objectives
To discuss some underlying
     neurobiological correlates of
     psychiatric conditions
     including the connection with
     the biogenic amines and
     faster neurotransmitter
     systems
To review the some basic
     psychopharmacologic
     principles                      Geriatrics, Royal Ottawa Mental Health Centre
To review drug interactions and
     serious adverse drug
     reactions




                                               T. Lau, MD, FRCPC, MSc., Assistant
                                              Professor, UNIVERSITY OF OTTAWA
“We have to ask ourselves whether medicine is to
  remain a humanitarian and respected profession or
  a new but depersonalized science in the service of
  prolonging life rather than diminishing human
  suffering”

                 Elisabeth Kubler-Ross
      (Swiss-American psychiatrist and author )
1.   To help prepare for the LMCC
     exam Part 1.
2.   To review the biogenic amine
     neurotransmitter systems
3.   To review the pharmacologic
     management of depression,
     bipolar disorder and schizophrenia
4.   To discuss each of the medication
     classes and representative
     examples.
5.   To review drug interactions and
     serious adverse drug reactions
1. Names and classes of medications
2. Pathways and actions of biogenic amine neurotransmitters
3. Mechanism of action of the common medications (eg SSRI’s,
   TCA’s, Antipsychotics etc.)
4. Generally be aware of the different pharmacological options
   for the three most common psychiatric conditions
5. Principles on how to start medications and follow their
   management over time.
6. Be aware of some significant adverse side effects
   SECTION 1. Intro
     History of Psychopharmacology
     Neurons & Neurotransmitters
   SECTION 2. Specific Disorders and Algorithms
     Depression and Anxiety
     Bipolar Disorder
     Schizophrenia
   SECTION 3. Specific Medications
     Antidepressants
     Mood stabilizers
     Antipsychotics
   SECTION 4. Drug Interactions
1. History of Psychopharmacology
2. Some Principles of Pharmacology
3. Neurons & Neurotransmitters
                Psychopharmacology
                                               Noradrenergic and
    Mono-amine oxidase            Atypical
                                              specific serotonergic
         inhibitor              Antipsychotic
                                                 antidepressant
       MAOI                           AAP         NaSSA
 AP

1950       1960      1970         1980          1990       200I


   TCA                         SSRI                     SNRI
Non-selective            Selective serotonin           Serotonin
 tricyclic AD            re-uptake inhibitor           noradrenaline
                                                       re-uptake
                                                       inhibitors
                                   Antipsychotics
•Antidepressants
  •TCAs (tertiary, secondary)        “major tranquilizers”
  •MAOIs/RIMAs                       Typical (1st generation)
  •SSRIs                             Atypical (2nd generation)
  •SNRIs                           Sedative/hypnotics
  •SARI                              “minor tranquilizers”
  •DRI                               Benzos
•Mood stabilizers                    barbiturates
  •Lithium
                                   Cognitive Enhancers
  •Anticonvulsants
  •Atypical APs                      AchEI
                                     NMDA receptor
                                      antagonists
Pinson and Gray Psychiatric Services 2003
   Pharmacology
     is the study of how drugs interact with
      living organisms to produce a change in
      function.
       Pharmacokinetics describes the effect of
        the body on the drug (e.g. half-life and
        volume of distribution).
       Pharmacodynamics describes the drug's
        effect on the body (desired or toxic).
   Psychopharmacology
     is the study of how substances that
      crosses the blood-brain barrier affect
      behavior, mood or cognition.
Downstream signal
transduction
1. Different receptors for
   same ligand
2. Different effects at
   dendritic soma and axon
3. Different effects pre and
   post synaptically
4. Receptor desensitization
   and localization- changes
   over TIME.
5. Different pathways and
   function
   If, in a disease state, there is too little, the
    treatment goal is to raise it.
     Eg. Depression with serotonergic/noradrenergic
      underactivity, antidepressants increase
   If, in the disease state, there is too much, the
    treatment goal is to block it
     Eg. Psychosis with overactivity of the mesolimbic
      pathways, antipsychotics decrease, (dopamine
      antagonists)
   Monoamines
     Catecholamines:
        Dopamine, Norepinephrine
     Indolamines: Serotonin,
     Histamine
     Acetylcholine
   Amino acids:
     glutamate, GABA, glycine
   Steroid hormones
     estrogen, androgen, corticosteroids
   Gases: nitric oxide
   Feedback: cannabinoids
   Peptides and proteins:
     opioids, endorphins, GH, CCK, PRL,
       angiotensin II, oxytocin,     calcitonin,
       insulin, glucagon.
   “Top down”
       Sleeping pills
       Sedatives
       Anti-convulsants
       Mood stabilizers
       Alcohol
   “Bottom up”
     Antidepressants
     Antipsychotics
NA, DA and 5HT Synthesis
Noradrenaline Deficiency Sydrome
                   • Deficiency syndrome
                     – Impaired attention
                     – Problems
                       concentrating
                     – Deficiencies in
                       working memory
                     – Slowness of
                       information
                       processing
                     – Depressed mood
                     – Psychomotor
                       retardation
                     – Fatigue
Noradrenaline Deficiency Sydrome
• Deficiency Syndrome
  •   Sleep problems,
  •   anxiety,
  •   obsessions,
  •   irritability,
  •   impulse control problems,
  •   appetite disturbance
4 pathways in the
  brain
  1. Mesocortical
  2. Mesolimbic
     (pleasure pathway)
  3. Tubero-
     infundibular
  4. Substantia Nigra
   Dopamine deficiency
     Depressed.
       Anhedonia, no motivation,
        procrastination and the inability to feel
        pleasure. Difficulty getting up in the
        morning. Problems concentrating
     Hypersomnia
     Parkinson’s
     Prone to form addictions,
       a need for caffeine or other stimulants,
        and gaining weight.
   Dopamine Excess
     Psychosis
     Aggression
     Hypervigilance
•   Differential Diagnosis
     1. Mood disorders

     2. Anxiety

     3. Psychosis

•   Treatment Algorithms
     1. Depression

     2. Bipolar Disorder

     3. Schizophrenia
        Differential Diagnosis of Mood
                   disorders
• Major depressive disorder
• Dysthymic disorder
• Depressive disorder NOS
    • (PMDD, Minor depressive disorder,
      RBDD, postpsychotic depressive
      disorder of schizophrenia, etc.)
• Bipolar I disorder
    • (including mixed episodes)
•   Bipolar II disorder
•   Cyclothymia
•   Mood disorder due to a GMC
•   Substance induced mood
    disorder
    Differential Diagnosis of Anxiety
•   Social phobia
•   Specific phobia
•   Generalized Anxiety Disorder
•   Post Traumatic Stress Disorder
•   OCD
•   Panic with and without agoraphobia
•   Separation anxiety disorder
•   Associated w depression / psychosis
•   Somatoform / Dissociative disorders
•   Personality disorder
•   Substance and general medical exclusion
Differential Diagnosis of Psychosis
• Mood D/O
   • Depression or Mania with psychosis
• SCZ
   • Schizophrenia, Schizoaffective,
     Schizophreniform
• Brief Psychotic Episode
• Delusional disorder
• Dissociative D/O
• Delirium
• Personality Disorder
• Substance and General Medical
  Exclusion
                        Initiate treatment with
                        SSRI, SNRI, NRI, other




Partial or no response after 4-6
wks of tx at adequate dosages              Inadequate response
R/A Diagnosis. Optimize dose




                                                      Augment
                 Switch to new                                                   Combine 2
                                                     1st Lithium
              antidepressant from          2nd   atypical antipsychotic     antidepressants from
                a different class                 3rd Lamotrigine             different classes
                                                   4th Thyroid T3


      Consider psychotherapy at              Consider ECT at any time particularly when
                                                      Very severe depression
      any point particularly with
                                                       Not eating or drinking
       early childhood trauma                                Catatonia
                                                             Psychosis
                                                            Suicide Risk
                                                   Med Intolerance / Pregnancy
                       Determine Phase of illness




       MANIA                 MIXED                  DEPRESSION                    EUTHYMIA


      Lithium                                 1) Lithium (for Cade’s                Lithium
       Epival                 AAP             disease)                                AAP
                             CMZP             2) Mood Stabilizer (Li, VPA,         ?Lamictal
Typical and Atypical                          AAP) plus Antidepressant
  Antipsychotics                              3) Lamotrigine
        ECT                                   4) Seroquel Monotherapy
                                              5) ECT




                                             Consider ECT at any time particularly when
                                                      Very severe depression
                                                       or uncontrolled mania
                                                       Not eating or drinking
                                                             Catatonia
                                                             Psychosis
                                                            Suicide Risk
                                                   Med Intolerance / Pregnancy
APA Schizophrenia Guidelines 2004. Schizophrenia Tx Algorithm
Schizophrenia Tx
Algorithm
   Antidepressants       Mood stabilizers
       SSRI’s              Lithium
       SNRI’s              Epival
       SARI’s              Lamotrigine
       NaSSA’s           Antipsychotics
       NDRI                  Clozapine
                              Olanzapine
       TCA’s
                              Risperidone
       MAOI
                              Quetiapine
       RIMA’s                Ziprasidone
       Novel Agents
1. SSRIs (Fluoxetine, Fluvoxamine, Paroxetine,
   Sertraline, Citalopram, Escitalopram)
2. SNRIs (Venlafaxine, Des-Venlafaxine,
   Duloxetine)
3. SARIs (Trazodone)
4. TCAs (Clomipramine, Amitriptyline, etc)
5. MAOIs (Nardil, Parnate)
6. RIMAs (Moclobemide)
7. Dopamine agonist (Mirapex)
                  5HT reuptake inhibition

Increased availability of 5HT in synapse (and somatodendritic areas)


    Increased activity of 5HT 1A autoreceptors acutely
    and decreased firing rate (negative feedback loop)

   Desensitization of presynaptic 5HT1A autoreceptors
   Return of normal firing rate with ongoing decreased
   reuptake.

                  Increased 5HT release and
                  neurotransmission
                  NE reuptake inhibition

Increased availability of NE in synapse (and somatodendritic areas)


    Increased activity of alpha2 autoreceptors acutely
    and decreased firing rate (negative feedback loop)

   Desensitization of presynaptic alpha 2autoreceptors
   Return of normal firing rate with ongoing decreased
   reuptake.

     Increased NE release and neurotransmission
     Downregulation of beta adrenergic receptors
     Sensitization of alpha 1 adrenergic receptors
   Prozac (Fluoxetine)                                     [Bech BJP 2000, Beasley JCP 2000]
     Longest t ½, ~15 days, active metabolite, elderly watch for SIADH, EPS. Inhibitor of
      2D6. Norfluoxetine 6 week washout. Can be problematic b/o of this.
   Paxil (Paroxetine)                                      [Wagstaff CNS drugs 2002]
     Shortest half life, some anticholinergic ASE, no metabolites, high risk of
      discontinuation syndrome. Substrate and inhibitor of 2D6 leading to non-linear
      pharmacokinetics
   Luvox (Fluvoxamine)                                     [Edwards BJP 1994]
     Interacts with coumadin. Least protein bound, no metabolites, no chiral center,
      weakest potency, sedating. Inhibitor of 1A2 and 3A/4
   Zoloft (Sertraline)                                     [Perry CNS Drugs 1997, DeVane
                                                            Clin Pharmaco 2002]
     Needs to be taken w food, DA activity: EPS and active metabolite, few drug
      interactions, can cause diarrhea and heartburn. Dose dependent variable
      neurotransmitter effects.
   Celexa (Citalopram)                                     [Keller JCP 2000, de Lima EBMH
                                                            2001]
     Most selective. Few drug interactions. Doesn’t effect INR (coumadin).
   Cipralex                                                [Burke JCP 2002]
       escitalopram
       S-enantiomer of Celexa. More of a dose dependent response curve due to differential binding at
        the allosteric and active drug site
   Pharmacodynamics
     Blocks 5 HT reuptake
     5HT 1A antidepressant anxiolytic
     5HT 1B food intake/temp
      regulation
     5HT 1C sensory
     5HT 1D anti migraine
     5HT 2A sleep disruption/sexual
      ASE, suicide R-changes, EPS,
     5HT 3 nausea
   Indications:
     MDD, dysthymia, OCD, PD, SP,
      PTSD, GAD, BN, Pain d/o, migraine,
      FM, selective mutism,
      autism/Tourette’s
   T     Tremors                                          GASH:
   H     H/A’s 20-30%                                       •GI (upset, N/D/C,
   E     Euphoria 8% MDD, 50% BAD
   N     Nervousness (agitation, dizziness,
                                                             bleed 1:8000)
          restlessness)                                      •Activation / Anxiety,
    E     Endocrine (SIADH, galactorrhea)

                                                             •Sexual dysfxn / Sleep
   W     weight gain
   A     anorgasmia and other sex problems                  disturbance / Sedation
          20-50%)                                            / Seizure 0.2%,
   G     GI upset, GI bleed (age>85, prev GI bleed)
   E     Excretions                                         •Head ache
   S     Sleep disturbance (REM suppression
          except luvox, inc awakenings, nocturnal
          myoclonus), sedation                            In the elderly, >85 or previous GI
                                                           bleed increased risk of GI bleed
   75% tolerate SSRI’s w no ASE’s                         [Dalton CNS Drugs 2006].
                                                           Retrospective data base reviews
   25% ASE disappear by day 14 (most w/I 3-4d).           limited by confounders including
    ~10% do not develop tolerance                          NSAID use.
   5HT syndrome, discontinuation syndrome                Increased risk of fracture in those
                                                           over 50 OR=2.1, falls OR 2.2
                                                           [Richards AIM 2007]
   Pharmacology of 1, 2 or all 3                    Few drug interactions
    monoamines, depending on the dose
    (Harvey AGP 2000)                                  May be safer if combined with
                                                        coumadin
   At low doses 5HT
                                                       Mirtazapine or Nefazadone may block
     (same ASE’s: nausea, agitation, sexual
      dysfxn, insomnia)                                 some 5HT effects
   At medium to high both 5HT and NE                ASE’s (E vs placebo) [ISDNSSH]:
    Reuptake blockade                                  Insomnia(18vs10%), somnolence 17-
     Watch for HTN, severe insomnia,                   23 vs. 8-9%), dizziness (19vs 8%),
      agitation, nausea, H/A, EPS                       anxiety (XR better), dry mouth (22 vs
   At very high doses all three                        11%, 12 vs. 6% XR), nausea (31-37 vs.
     May be useful in melancholic, severely            11-12%), h/a (24% comparable to
      depressed inpatients and those refractory         placebo), sweating (<75: 5-6%
      to other antidepressants                          =placebo, 225: 12.4%, 375 19.3%),
   Steady state [ ] ~3d, t ½ ~5hrs, ~11h for           sexual dysfxn (12-16 vs <1%),
    active metabolite (ODV ~56% of any                  sustained HTN (<75: 1%=placebo, 225:
    given dose), unless XR.                             2.2, 375: 4.5%), withdrawal effects
                                                        common
   Metabolized by 2D6, weak inhibitor of
    2D6
   Desvenlafaxine (Pristiq) AKA, O-            The most commonly observed
    desmethylvenlafaxine,                        ASE (incidence >= 5% and at least
   Desvenlafaxine is a synthetic form           twice the rate of placebo in the 50
    of the major active metabolite of            or 100 mg dose groups) were
    venlafaxine (Effexor)                        nausea, dizziness, insomnia,
   It is being targeted as the first non-       hyperhidrosis, constipation,
    hormonal based treatment for                 somnolence, decreased appetite,
    menopause.                                   priapism, night terrors, anxiety,
                                                 and delayed ejaculation.
   Theoretically useful for slow 2D6
    metabolizers                                Nausea was consistently the
                                                 most common complaint (30-
                                                 50% vs placebo 9-11%) and the
                                                 most common reason for
                                                 discontinuation.
   Dual “balanced” 5HT and NE
    reuptake inhibitor (still 2:1 in vivo)
   Higher potent affinity for 5HT and
    NE transporters than Effexor
   T1/2= 10-15 hours
   SE consistent with NE potentiation
    (BP, HR)
   Cases of hepatitis/jaundice (LFTs up
    20x)
   Moderately potent 2D6 inhibitor
   Dosing 20-60 mg daily with food



                                       Raskin J et al. Pain Med. 2005;6:346-356.
   Trazadone
     T ½ is 7-8 hrs
     Trazadone is a potent 5HT 2A/C antagonist, at higher doses weak SSRI
     Metabolized by CYP 3A4, 2D6, 1A2
     Active m-CPP metabolite is a 5HT2C agonist with anxiogenic properties-
      found in low levels
     S/Es: dizziness, postural hypotension, priapism
     Hypnotic (inc. slow wave sleep / dec. REM sleep)
     May be arrhythmogenic in cardiac patients
         Arrhythmias identified include isolated PVC's, ventricular couplets, and in 2 patients short
          episodes (3 to 4 beats) of ventricular tachycardia
     Dosing: sleep 12.5-150 mg/day, antidepressant 150-600 mg/day
   Sedation may be higher at
    lower doses
   More than one mechanism of
    action
   Consider for depression with
     Anxiety, Agitation
     Insomnia, SSRI induced sexual
      dysfxn, nausea, GI distress
     Panic, Weight loss
     Severe depression
   May be useful in tx resistance
    as an augmentation agent
   Low likelihood of drug interactions
    • Adverse clinical effects of drowsiness
      (23% versus 14%), excessive sedation
      (19% versus 5%), dry mouth (25%
      versus 16%), increased appetite (11%
      versus 2%) and weight increase (10%
      versus 1%).
    • [SWD]
   Pharmacology
     Blocks alpha 2 auto and 5HT-alpha 2
      heteroreceptors
     Blocks 5HT2 (anxiety, sleep)
     Blocks 5HT3 (nausea)
     Blocks H1
   Start 15mg qhs increase to 30-45 mg/d
   unicyclic aminoketone
   Indications:
     MDD, BAD depression, smoking cessation, ADHD, SAD, cocaine abuse.
   Mechanism of action
     Through noradrenergic mechanisms, actually has poor affinity for
      Dopamine reuptake pump, probably through a GABA interneuron with 5
      HT involved.
   Therapeutic profile
       Retarded depression, hypersomnia (NA depression)
       Nonresponder /can’t tolerate 5HT agents
       No sexual dysfxn/wt gain. Safe in elderly with cardiovascular disease
       Cognitive slowing/pseudodementia
       50% response in stimulant responders in ADHD
       Negative effects (seizures) reported in eating disorder patients
   H     H/A*,
   E     excitement*, anxiety                           Recommended dose 150-300
                                                          mg/d single SR dose. Start at
   L     lowers seizure threshold                        100 and titrate upwards to
         seizures 0.1% < 300 mg/d, 0.4% > 400 mg/d       clinical effect. T1/2 = 10-
                                                          14h/SR 21h, Time to peak
   P     p450 interactions                               plasma [ ] =2-3h, Steady
                                                          state levels b/o 3 metabolites
   I     insomnia*, irritability*                        = ~10 days.
   N     nausea*                                        Inhibitor of 2D6, substrate of
                                                          2B6, has three active
   G     GI distress                                     metabolites
   A     agitation, amphetamine like                    NDRI (low NA, high DA, also
          effects, allergic reactions                     some 5HT, alpha 2, M1)
                                                         Labs may give false positive
   C     constipation, cardiac palpitations              urine amphetamines
   T     tremor, tinnitus
                          Relatively
                           5HT>NE
                         More other
                       receptors ASEs

   Tertiary Amines
     Imipramine, Amitriptyline,
      Doxepin, Clomipramine             CYP 1A2
   Secondary Amines                      CH3
     Desipramine, Nortriptyline,
      Protriptyline
   Tetracyclics
                          NE>5HT
     Amoxapine          Fewer side
     Maprotiline          effects      CYP 2D6
   Anticholinergic
     Dry mouth, blurred vision, urinary retention, confusion
   Orthostatic Hypotension
     Alpha 1 adrenergic blockade, transient
   Cardiac Conduction Changes
     Quinidine like type 1a antiarrhythmic effect
     Depressed ST and blunted T wave. Prolongation of PR, QT, QRS
     Tertiary amines and hydroxylated metabolites worse
   Endocrine
     Weight gain, elevation in blood sugars, SIADH
   CNS
     Sedation, myoclonic twitches, tremors, seizures (worse with maprotiline)
   Allergy
     Photosensitivy, jaundice
   Psychiatric
     Switch to mania in 50% of Bipolar vs. 1-7% Unipolar
   Sexual Dysfunction
     Related to anticholinergic, alpha 1 blockade, 5HT reuptake inhibition and
      altered dopamine
                                         Common ASEs
                                             Orthostatic hypotension
   MAO – oxidative deamination              Weight gain
    of amines 5HT, NE, DA
                                             Sexual dysfunction
   Discovered accidently in tx of
    TB (IPZ)                                 Ankle edema
   MAOIs structurally similar to        Other Side Effects
    catecholamines
                                           Insomnia with daytime sedation ‘Nardil
   MAOIs block monoamine
    oxidase inhibitor permanently           Nod’
    and irreversibly                       Myoclonus, tremor and akathisia,
   Suggested to be more                    parathesias
    effective in MDD with atypical         Dry mouth and urinary retention
    features
   Divided into 2 groups                Rare but serious
     Hydrazine (Phenelzine-Nardil)        Hypertensive crisis (tyramine cheese
      and Non-Hydrazine                     reaction-displaces NE in vesicles).
      (Tranylcypromine-Parnate)
                                            Guidelines is <6 mg
     Nardil-more sedating
     Parnate-amphetamine like             Blood dyscrasias
      qualities, can be activating         Hepatotocity
                                           Teratogenecity
   Selective and reversible inhibitor of monamine
    oxidase subtype A (RIMA)
   Efficacy shown in depression and social phobia
   D0sage: initiate at 300 mg divided. Maximum dose
    600 mg/day. Looses its selectivity above 900 mg/day
   Few side ffects. Can be useful in patients who cannot
    tolerate the GI ASE of SSRIs/SNRIs
   Pharmacokinetics: Short t1/2 of 1-2 hours. 1-2 day
    washout.
   No cheese reaction at 600 mg/day [150 mg
    tyramine=3kg cheese raises SBP by 30mmHg]. Dietary
    restrictions not necessary <600 mg/day.
   Inhibition of MAO-A returns to normal within 1 day of
    cessation
   Metabolized by flavin-containing mono oxygenase and
    CYP 2C19
   Fatalities reported with combination with SSRIs Lancet
    1993. Do not combine with MAOIs, DM, Ephedrine,
    meperidine
   Serotonin Syndrome and HTN
   Metaanalysis of Moclobemide with SSRIs in
    MDD. Papakostas and Fava
   Can J. Psych Oct 2006
   Main Finding n=1207 (risk ratio 1.08; 95%
    confidence interval, 0.92 to 1.26; P = 0.314)
   Limitations
     The absence of comparative studies involving
      citalopram and escitalopram precludes
      generalization to all SSRIs.
     Based on 12 RCT Comparison trials with no placebo.
      The lack of placebo comparison groups means that
      no conclusion can be made about the assay
      sensitivity of these trials.
     There were no outcome data for the subset of
      patients with atypical depression
Lithium
Epival
Lamotragine
Carbamazepine
Gabapentin
(more used for anxiety or neuropathic pain)
   Simplest solid element                 Pharmacology
   Natural salt discovered in 1817
   First described by John Cade             Increases release of 5HT
    (1949) to have antimanic                 Blocks release of NE and
    properties                                DA
   Pharmacokinetics
     100% absorbed, 0% protein              Blocks receptor mediated
      bound                                   actions of several hormones
     T ½=24-36 hrs                           on adenylate cyclase (eg.
     No metabolites                          ADH and TSH)
     100% renal excretion with renal
      excretion interactions                 Possible stabilization of
                                              catecholamine and
                                              acetylcholine receptors
                                             Alters distribution s of other
                                              ions, Mg 2+, Ca 2+, K+, Na+
   Responders
     Classic euphoric mania, infrequent episodes with full interepisode
      recovery, FHx of Li response& BAD, PHx of Li response,
   Non-responders
     Severe, dysphoric, mixed, psychotic mania, rapid cycling, adolescent, >3
      episodes, substance abuse, 2o mania
   Dosing
     Adult- 600-1500 mg/d (0.5-1.2). Geriatric- 150-600 mg/d (0.3-0.8)
     Once pt is stabilized switch to once daily dosing. Check plasma levels 5
      days after start then twice weekly for the 1st two weeks then weekly for
      the next 2 weeks, then if stable @ clinical discretion (at least every 6
      months). Also check lytes, BUN, Cr, regularly, and TSH (periodically after 3
      months and every 6-12 months afterwards)
                                Levels
                                  Increased by NSAIDS, thiazide diuretics, ACEI,
   T      Tremor                  tetracycline, anticonvulsants
   H      Hypothyroid            Also consider decreased clearance with aging,
   E      CG changes              renal disease, dehydration, low salt diet
   M      uscle weakness         Decreased by osmotic diuretics (eg. mannitol),
   A      lopecia                 carbonic anhydrase inhibitors, caffeine,
   G      I upset                 theophylline, high salt diet
   I      ncreased WBC           Pregnancy (increased plasma volume but also
           (transient)             GFR).
   C      ardiac arrhythmias  ASE’s
   W      eight gain            Poly’s (60%), N, abdo pain, V, D, vertigo, muscle
   A      cne                    weakness, fine tremor M>F 54 vs. 26%, wt gain
   N      eurological            F>M (47 vs 18%), hypothyroidism (5-15% F>M
   D      rinks/ diabetes        (recent study 37 vs. 9% F>M, predictor=wt gain).
           insipidus             Toxicity: usually starts w GI then tremor, then
   GPWITH                        thirst and inc u/o, then drowsiness, ataxia, tinnitis,
   (GI, Polys, wt gain, incr     blurred vision.
    WBC, tremor,
    hypothyroid)
   Potentiation of GABA
   Interactions
     Inhibits metabolism of benzos, carbamazepine (Inc levels of CBZ-E metabolite).
      CBZ by induction dec VPA levels
     Increases plasma levels of prozac, TCA’s, Lamotragine.
     May worsen tremor w Li, VPA can increase levels of Li (Li can decrease levels of
      VPA)
     VPA displaces protein bound-ASA
   Begin at 250mg BID or TID to reduce ASEs. Dosage range 750-3000 mg/d.
   Poor correlation of clinical effect w plasma levels (350-800 umol/L). Check
    levels after 3days, then weekly for the first 2 weeks and then with clinical
    discretion
   Labs: CBC, INR, PTT, monthly for 6 months then q 6 months. LFT’s monthly
    for 3 months then q 3-6 months. Could also check Lipase.
   T   tremor (10-29%)
   U   unsteadiness
   R   rashes
   N   nausea (20%) / GI upset
   S   sedation (31%)                       Common ASE: N, V,
   O   oligomenorrhea / PCO                  indigestion, usually
        (menstral irreg in 45%)               transient and rarely require
   B   blood dyscrasia                       d/c. 11% discontinuation
        (thrombocytopenia, anemia)            rate in trials.
   A   alopecia                             Common:
   L   LFT elevation (up to 44%)            [WITH GST]
   D   dysarthria                           Wt gain,
   &                                        Irregular menses,
   F   fat (59% mean wt gain 8-21 kg
        F>M), (also overestimates serum
                                              Teratogen,
        FFA)                                 Hair loss,
   A   ammonia levels can rise              GI, Sedation (cognitive
   T   teratogen (5-15%)                     dulling,), Tremor
   Indications
     May be effective in bipolar depression, may also cause a switch.
     Not effective in treating mania
   Pharmacology
     Works thru voltage sensitive Na channels unlike others no GABA effects.
     No clear clinical response correlation with levels
   Clinical
     Start 25-50 mg/d and titrate gradually every 2 weeks up to 250 mg BID.
      Therapeutic range appears to be 50-200 but some additional benefit seen
      occasionally by inc dose to 500 mg/d.
     Starting low and going slow may decrease risk of rash
     Lamotrigine decreases levels of Epival
     Epival increases Lamotrigine’s T ½
     Use doses below 150 mg/d (half the dose)
     CBZ decreases t ½ (double the dose)
     Safe in combination w Li
R rash (10-25%-cf 5% PCB, 2-3% require drug d/c). SJS
  and TEN higher in epileptic patients. Serious
  rash=0.3% adults/1% in children. With slow titration
  risk was reduced to 0.01% comparable to other
  anticonvulsants.
A activation (3-8%), ataxia
S spaced out (cognitive slowing), sedation, sleep
  disturbance
H H/A, hypersensitivity reactions, Nausea,
   Similar to GABA in structure
   Some evidence for efficacy in neuropathic pain, RLS
   Evidence for efficacy in social phobia
   Maybe an effective anxiolytic
   Pharmacokinetics
     Not metabolized, safe in od, few ASE
     Fatigue at higher doses, inc appetite, ataxia, wt gain, hypomania,
      if stop to quickly can see sx
     Can be inc rapidly, well tolerated, but watch for renal failure,
      ataxia and delirium: 900-1800 mg/d.
     Case reports of TD
   Evidence for efficacy in RLS
   New related med pregabalin has shown efficacy in GAD
   Similar in structure to tricyclics
   Multiple ASE (lots of receptors, induction of hepatic
    metabolism eg. 3A/4 OCP), autoinducer (half life shortens 3-5
    weeks later)
     ASEs:
   Active metabolite 10,11 epoxide CPZ (VPA blocks further
    breakdown),
   Poor correlation between blood level and clinical effect
   Regular B/W: transient leukopenia (agranulocytosis 1/10-25
    000, fatality 1/22 million), contraindicated w Clozaril
•Typicals
   •Haldol
   •Chlorpromazine
•Atypicals
   •Risperidone
   •Paliperidone
   •Olanzapine
   •Quetiapine
   •Ziprasidone
TYPICAL ANTIPSYCHOTICS                             ATYPICALS
• Phenothiazine antipsychotics                       • Amisulpride,
    • Chlorpromazine, Fluphenazine,                    Aripiprazole,
      Mesoridazine, Perphenazine,                      Clozapine,
      Prochlorperazine, Promazine,                     Olanzapine,
      Thioridazine, Trifluoperazine                    Quetiapine,
•   Thioxanthene                                       Risperidone/Paliperid
    • Thiothixene [Navane]                             one}, Sertindole,
                                                       Sulpiride,
•   Dibenzodiazepines
                                                       Ziprasidone, Zotepine
    • Loxapine (Loxitane) Clozapine (Clozaril)
•   Butyrophenones
    • Droperidol (Inapsine) Haloperidol (Haldol)
•   Indolone
    • Molindone (Moban)
•   Diphenylbutylpiperidine
    • Pimozide (Orap)
High potency group        Low potency group

D2 blocking action is        Fewer Extrapyramidal
strong.                      symptoms
                             More side effects on
More Extrapyramidal          autonomic nerves and
symptoms                     circulatory system.
Few side effects on          Sedative action is strong.
circulatory system.


Phenothiazines               Phenothiazines
           fluphenazine        chlorpromazine
           perphenazine        thioridazine
Butyrophenones
           haloperidol
   Response
     70% Positive Sx in SCZ
     BPRS, PANSS
   Remission
     <10%
   NNT’s with CI’s.
   Risperidone
     Used in Schizophrenia, psychotic disorders, dementia (BPSD),
      mood disorders (mania and depression augmentation) [latter 2 at
      lower doses <2 mg/day]
     Higher rates of EPS compared to other SGA. Prolactin elevation.
   Paliperidone
     Used in Schizophrenia, mania. Has anti alpha 1 and 2 adrenergic
      effects (more cardiac concerns). Extended release, hydroxylated
      risperidone.
   Olanzapine
     Used in Schizophrenia, psychotic disorders, mood disorders
      (mania, depression, maintenance Bipolar). Causes weight gain
      and metabolic syndrome. Can also cause glycemic changes.
   Quetiapine
     Very sedating. Used in Schizophrenia, psychotic disorders,
      mania and for bipolar depression (BOLDER 1&2) and possibly
      unipolar depression. Sedating and can cause orthostatic
      hypotension.
   Ziprazodone
     Has 5HT 1a properties; therefore may help with depression
   Clozapine
     Many side effects including risk of agranulocytosis which leads to
      regular and frequent blood tests. Difficult to use in the elderly
      because of anticholinergic/antiadrenergic ASEs. Associated with
      weight gain and metabolic syndrome.
   Indications
     SCZ, Mania, BPSD, Depression augmentation.
   Efficacy
     Acute (3 PCT’s)
       N= 160, 6 wk DB, flex dose < 10 mg (avg. 7.8), vs. Haldol
        < 20 mg. Risp > PCB BPRS. SANS, CGI.
       N=1356, fixed doses (1,4,8,12,16 mg/d) vs Haldol 10
        mg/d or PCB. Dosed Risp > 1mg > PCB (optimal
        response 4-8 mg), PANSS, BPRS.
       N=513, 4 doses (2,6,10 or 16 mg/d) w Haldol 20 mg/d or
        PCB. Risp > PCB PANSS, BPRS, CGI although 2 mg not
        always reached stat sig.
       Efficacy in once daily dosing also established.
   RESHAPE
       R Restless legs, Rhinitis
       E EPS,
       S Somnolence
       H H/A
       A appetite / agitation
       P PRL
       E edema, peripheral
   Some patients tolerate it better than risperidone
   Hyper PRL with low E2 may accelerate
    osteoporosis
   Like Risperidone, may cause more motor ASE
    than other SGAs
   Trilayer tablet
   Aripiprazole
     (Abilify, Abilify Discmelt) is an atypical antipsychotic used
      for schizophrenia, bipolar disorder, and augmentation for
      clinical depression.
   Pharmacology
     Partial agonism at D2R
     Partial agonism of 5HT1A
     Blockade of 5HT2A
     Alpha 1 blockade (ASE)
   Drug interactions
     Metabolized by 2D6 and 3A4. Ketaconazole may increase
      dose.
   Dosing:
     15-30 mg/day
     For some less may be more: those not acutely psychotic 2.5-
      10 mg/d to avoid akathisia and activation.
     For some more may be more: some may benefit from doses
      above 30 mg/day.
     Due to its long life may take longer to reach steady state.
   Clinical Pearls:
     Weight gain not as common and is less sedating
   ASEs:
     dizziness, insomnia, akathisia, activation, N/V
   Indications
     Treatment resistant psychosis, mania,
      depression
     Landmark study Kane et al (AGP 1988) of tx
      resistant patients. Markedly lower rates of EPS
     CATIE confirmed superiority (although it was an
      open phase of the study)
   Baseline B/W:
     CBC w diff, lytes, BUN, Cr, TSH, ECG, LFT’s,
      CXR. Consider HIV, Tb testing. Check CBC
      qweekly for 26 weeks then biweekly afterwards
     Contraindicated w CBZ b/o transient
      leukopenia.
W weight gain
A agranulocytosis(<0.5, 0.7 %) cytopenia(<1.5, 3 %).
   ~90% in first 26 weeks. Higher risk in those >50
   Guidelines: CBC weekly x 26 weeks then every two weeks or 4 weeks after D/C. Evaluate twice
   weekly and CBC if WBC (2.0-3.5), ANC (1.5-2.0), single fall WBC or sum of falls >3.0 reaching a level <
   4.0, a single fall or sum of falls of ANC > 1.5 reaching a level of <2.5, or flu like symptoms. If below
   WBC 2.0, ANC 1.5, Clozapine should be discontinued and patient followed closely. Cultures and
   reverse isolation if WBC <1, ANC<0.5
T tachycardia (up to 25%)
C2 constipation (14%), cardiac other (ECG changes, pericarditis, myocarditis)
H hypotension (dizziness 19%) / H/As (7%)
E EPS (rare, including NMS)
S4 Sedation (39%), Seizures (<300mg 1-2% like other APs, 600-
  900 mg 5%), Sialorrhea (31%), Sugars (diabetes 33%),
Sedation and hypersalivation sometimes mistaken for Parkinsonism
   Indications
     SCZ, BAD-mania, acute agitation, ?Dementia (BPSD)
     Superior effects on cognition in SCZ
     ?Superior effects on mood
   Efficacy in SCZ
     Acute
       2 x 6 wk PCT n=335, n=431, fixed doses, 10, 15 > PCB on
        BPRS, CGI. OLZP 15mg > Haldol 15 mg SANS.
       6 wk PCT 2 fixed doses 1 and 10 mg. 10 mg > PCB
        PANSS, BPRS, CGI.
       6 wk (n=1996) comparison dose range study OLZP 5-20
        (13.2 avg) mg, Haldol 5-20 (11.8 avg) mg, OLZP> BPRS
        (+neg cluster), PANSS neg, CGI. Also OLZP>H on
        MADRS but not validated in SCZ.
     Continuation
       3 DBC-extension/main trials. > PCB in the one trial,
        comparable or > than active comparators in 3 other
        studies.
SAD COST
   Somnolence
   Appetite / Wt gain
     (acute mean 2.8, chronic mean 5.4 kg,
      ?level @39 wks, may not be dose
      dependent)
   Diabetes, DKA, dry mouth
   Constipation
   Orthostatic hypotension
   Seizures
   Transaminase (ALT) / TG elevation
   Efficacy
     Acute 3 x 6 wk PCTs
       N=361, 5 fixed doses (75, 150, 200, 600, 750 mg),
        4 highest doses > PCB BPRS, CGI
       N=286, high/low titration up 750 mg/ up to 250
        mg), only high dose BPRS, CGI, SANS > PCB.
       N=618 2 fixed doses 450 vs 50 mg. 450 mg > PCB
        on BPRS, CGI, SANS.
       One study showed no improvement in SANS
        sim to Haldol.
     Comparison studies
       QUEST (Quetiapine
                experience safety tolerability)
       Mixed population
   SOLD
       Somnolence
       Orthostatic hypotension
       Liver transaminase elevations
       Dizziness / Dry mouth / Dyspepsia
   Ziprasidone (Geodon, Zeldox)
   Indications:
     schizophrenia, and acute agitation IM in schizophrenic patients, mania
      and mixed states associated with bipolar disorder.
   Pharmacology:
     Has high affinity for dopamine, serotonin, and alpha-adrenergic
      receptors and a moderate affinity for histamine receptors, as an
      antagonist. Has perhaps the most selective affinity for 5-HT2A
      receptors relative to D2 and 5-HT2C receptors of any neuroleptic.
     5HT 1A agonism
     Antagonism at histaminic and alpha adrenergic receptors likely
      explains some of the side effects of ziprasidone, such as sedation and
      orthostatic hypotension.
   Clinical Pearls:
     Increases QTC
     Should be taken with food to increase absorption
     Less weight gain (maybe even weight loss), risk of
      diabetes, dyslipidemia
     Efficacy maybe underestimated because it is usually
      underdosed (<120 mg/day)
     More activating that some of the other SGAs
     Has an IM form
Starting a medication
Adverse Side Effects
Serotonin Syndrome
Mechanisms Underlying Drug Levels
Drug Interactions
   FIRST (check diagnosis,
    comorbidity, medical causes)

   S   Safety (including drug-drug
        interactions)
   T   Tolerability (acute and long term
        potential ASE’s)
   E   Efficacy (response rate, relapse
        prevention, for your particular
        patient’s characteristics)
   P   Payment/cost
   S   Simplicity (dosing, blood work)
                                            Preskorn JCP 1997
   Cardiovascular
     [mainly antidepressants and antipsychotics]
     Arrhythmias (tachycardia, QTC prolongation), HTN, Hypotension,
      rarely myocarditis
   Hematological
     [mainly anticonvulsants and clozapine]
     Blood dyscrasia (anemia, agranulocytosis, thrombocytopenia)
   GI
     Dyspepsia, nausea, constipation or diarrhea, rarely: liver or pancreatic
      inflammation
   Neurological
     Dizziness, ataxia, blurred vision, dyskinesias, tremor
     Receptor mediated effects
   Drugs bind to more
    receptors than they ideally
    should
                                    Psychomotor activation
    Sedation/Drowsiness                  Psychosis                    Sexual dysfunction
        Weight gain                                                      Activating
                                         DA reuptake                     side effects
                                              `
                                          inhibition
                                                                          Insomnia
   Blurred vision                                          5HT2
                                                        Stimulation
    Dry mouth
   Constipation                                                               Nausea
 Sinus tachycardia      Ach block
                                       Antidepressant
 Urinary retention
Memory dysfunction
                                                         5-HT reuptake
                                                                          GI disturbances
                                                           inhibition    Activating effects

         Priapism                                NE reuptake
                               Alpha2 block
                                                  inhibition
                                                                    Dry mouth
                     Postural hypotension                        Urinary retention
                          Dizziness                              Activating effects
                      Reflex tachycardia                              Tremor
Adapted from Richelson E. Current Psychiatric Therapy. 1993;232-239
                  Anticholinergics

Red as a beet                Vasodilation
Dry as a bone                Dry mucous mbs, anhydrosis
Hot as a hare                Hyperthermia
Mad as a hatter              Delirium, hallucinations, agitation, cognitive
                             impairment
Blind as a bat               Blurred vision, worsens glaucoma, photophobia
Bowel and                    Constipation
Bladder loose their tone     Urinary retention,
And the heart goes off       Tachycardia
    alone

Also delayed or retrograde ejaculation
                                                 Memory impaired in Elderly




Tune et al. Am J Psychiatry 1992;149:1393-4.
Miller et al. Am J Psychiatry 1988; 145: 342-5
                                             PATHOPHYSIOLOGY
   1960—tryptophan and MAOIs
   1984—Libby Zion: meperidine,               Stimulation of 5-HT
    phenelzine and cocaine                       receptors in brain, GI tract and
   15% incidence in patients overdosing           vessels
    SSRIs                                      Drugs may stimulate receptors
   Toxic exposure surveillance system 2002     directly
    in the US                                    Tryptophan
   7,349 patients reported in 2002              Sumatriptan (Imitrek)
   93 deaths                                    Buspirone (Buspar)
   0.4 cases/1,000 patients—months on         or block reuptake and
    SSRIs                                       metabolism
   Oates JA (1960), Neurology 10:1076-          SSRIs
    1078; Asch DA (1988), N Engl J Med           Meperidine
    318(12):771-775                              MAOIs
   SSRIs
     Sertraline (Zoloft), fluoxetine (Prozac), fluvoxamine
      (Luvox), paroxetine (Paxil), citalopram
   Other antidepressants
     Trazodone, nefazodone, buspirone, clomipramine
      (Anafranil), venlafaxine (Effexor)
   MAOI
     Phenelzine, isocarboxazid (Marplan)
   AEDs
     Valproate (Depacon)
   Analgesics
     Meperidine, fentanyl (Duragestic), tramadol (Ultram),
      pentazocine (Talwin)
   Antiemetics
     Ondansetron (Zofran), metoclopramide (Reglan)

                                                              Boyer NEJM 2005
                                                          Boyer NEJM 2005

   Migraine
     Sumatriptan
   ABx
     Liezolide (Zyvox), ritonavir (Norvir)
   Abused drugs
     MDMA, LSD
   Dietary supplements
     Trypotphan, St. John’s Wort, ginseng
   Lithium, dextromethorphan
   REPORTED AGENTS INVOLVED
     Sertraline, fluoxetine (Prozac, Sarafem), fluvoxamine, paroxetine,
      citalopram, trazodone, netazodone, buspirone, clomipramine, venlafaxine,
      phenelzine, moclobemide (Manerix), isocarboxazid, divalproex (Depakote),
      meperidine, fentanyl (Duracesic, Sublimaze), tramadol, pentazocine,
      ondansetron, granistron (Kytril), metoclopramide, sumatriptan, sibutramine
      (Meridia), dexfenfluramine (Redux), fenfluramine (Pondimin), linezolid,
      ritonavir, tranylcypromine (Parnate), imipramine, mirtazapine (Remeron)
   SEVERE SS combos
     Phenelzine and
      meperidine
     Phenelzine and SSRIs
     Paroxetine and buspirone
     Linezolide and
      citalopram
     Tramadol and
      venlafaxine and
      mirtazapine
                                                     NMS
   Serotonin Syndrome                                    Fever, rigidity, neuroleptic use +
      Agitation/restlessness (most                       Altered mental status
       common)                                            Seizures, coma, catatonia
      Confusion                                          Mutism
      Hyperthermia                                       Dyphagia
      Tachycardia, HTN                                   Leukocytosis
                                                          Elevated CPK
      Autonomic instability
                                                          Myoglobinuria
      Diaphoresis                                        Decreased renal fxn
      Hyperreflexia                                      Dec TIBC (?epiphen)
      Myoclonus                                     Risk factors
      Ataxia                                          Underlying medical illness, young, M,
      Incoordination                                   recent dose inc, low TIBC, dehydration,
                                                        Lithium,
   Serious complications
                                                     Tx
      Sz, DIC, respiratory failure, inc               D/C neuroleptic, supportive
       temp, death                                      management, consider DA agonists,
                                                        ECT. If rechallenge >2/52

Same: autonomic instability (fever, tachy)
Different: SS- hyper reflexia, myoclonus, ataxia, incoordination, mydriasis active bowel sounds.
NMS- rigidity, dysphagia, dysarthria, incontinence, sialorrhea, SOB, EPS, markedly increased CK,
increased WBC/myoglobin, neuroleptic use
   Flu like symptoms, vertigo, dizziness and nausea, jolt
    like bursts several times throughout the day
   Differs from SSRI S/E
   Occur within 1-3 days after abrupt discontinuation of
    the SSRI- subsiding within two to several days after
    the last dose
   Most frequently cited with paroxetine and
    venlafaxine
   Term not to be confused with withdrawal seen in
    addiction
   Rx: taper the SSRI slowly or start another SSRI
   anticholinergic effects                         EPS
     peripheral, central                             parkinsonism, dystonia,
   sedation, falls / #’s                              akathisia, catatonia, NMS
                                                      Movement disorders. TD
   CVS
                                                      NMS
     QTC and conduction defects /
      repolarization delays                         Sexual dysfxn
     Highest w Thioridazine, Ziprasadone,            CPZ, thioridazine, risperidone
      Haldol (intermediate). K rectifier pump.
      QTC>480 ms. F>M. Elderly [>75] QTC            Seizures
      >430 ms RR of death 2.4 Nilsson                 Higher w low potency agents
      Eurospace 2006
     orthostatic hypotension,                      Miscellaneous
      tachycardia                                     Photosensitivity, Cholestatic
                                                       jaundice,
   Weight gain
     Variable (highest w Clozapine, OLZP)
   Diabetes / Metabolic changes
     Atypicals > Typicals 9% when controlled for age.
      Highest w Clozapine, OLZP.
   Hyperprolactinemia
   CVA’s/TIA’s and mortality when studied with AD
   Modifiable Risk Factors Affected by
    Psychotropics
       Overweight/obesity
       Insulin resistance
       Diabetes/hyperglycemia
       Dyslipidemia
       Newcomer JW (2005), CNS Drugs 19(Supp 1):1-93
   Nemeroff CB (1997), J Clin Psychiatry 58 Suppl 10:45-49; Kinon BJ et al. (2001), J Clin Psychiatry
    62(2):92-100; Brecher M et al. (2004), American College of Neuropsychopharmacology. Poster 114;
    Brecher M et al. (2004), Neuropsychopharmacology 29(suppl 1):S109; Package insert Geodon
    (2005); Package insert Risperdal (2003); Package insert Abilify (2005)
   Absorption
     Transporters, ATP dependent transporters, intestinal mobility, food, other
      drugs (acid-base, competition for active transport, drug-drug binding)
   Distribution
     Genes that encode proteins that bind drugs in the blood decreasing their
      bioavailability. Lipophilic tissues absorb drugs and slowly releases them as
      blood levels decrease
   Metabolism
       (some drugs may be pro-drugs)
       Phase I- CYP (liver and intestine)
       Phase II- UGT (liver)
       Others enzymes- Thiopurine s-methyltransferase (TPMT) and Vitamin K
        oxide receptor complex (VKORC1), etc.
   Elimination
     Kidney function, P-glycoprotein i.e. efflux transporters (Intestinal
      enterocytes)
   Age—>65 have 3 fold             P450 Enzyme System
    increase risk                     Located in liver, kidney, intestine, lungs, brain
   Polypharmacy                      Individual enzymes metabolizing >95% of all
   Lack of awareness of               drugs:
    cytochrome (CYP) 450              Subtypes:1A2, 2B6, 2C9, 2C19, 2D6, 3A4
    system is a problem.
   Most clinically
    significant interactions
    have been mediated
    through P 450
   Brown CS (2000), US
    Pharmacist.
Relative Importance of Cytochrome p450 in Drug
Metabolism - adapted from Shimada T J
Pharmacol Exp Ther 1994
   Drug interactions occur
    during phase
    1metabolism
     (oxidation, hydroxylation,
      methylation)
   Phase 2 metabolism
    prepares the compound
    for
     elimination by making it
      water soluble (e.g.,
      glucuronidation)
   www.fda.gov./cder/drug/drugreactio
    ns/default.htm.
    7% of Caucasian population
     have polymorphisms of CYP2D6
     isoform
    20-30% Asians CYP2C19
      Poor metabolizers (PM)
      Extensive metabolizers (EM)
      Ultra-rapid metabolism (URM)




Relative Importance of Cytochrome p450 in Drug
Metabolism - adapted from Shimada T J
Pharmacol Exp Ther 1994
Relative Importance of Cytochrome p450 in Drug Metabolism -
adapted from Shimada T J Pharmacol Exp Ther 1994
   3A ¾ (50%)             • 2D6 (20-25%)
   SUBSTRATES
                           •   SUBSTRATES
      B benzos
      E effexor                •   E effexor
      S sertraline             •   A AP’s,
      T tertiary amine,            antiarrhythmics       • 1A2 (10-15%)
       trazadone                •   T trazadone           •   SUBSTRATES
      C clozaril               •   C clozaril, codeine        • C clozaril, coumadin,
      L luvox                                                       caffeine
                                •   R risperidone
      O OCP                                                   • H haldol
                                •   O olanzapine
      N Nefazadone
                                •   P prozac, paxil            • A acetaminophen
      E Erythromycin
   INHIBITORS                  •   S secondary                • T tertiary amines,
                                    amines                           theophyline
      N nefazadone,
       norfluoxetine                                      •   INHIBITORS
      F fluoxetine        •   INHIBITORS                      • L luvox
      L luvox                  •   P2 paxil, prozac
                                •   B buproprion               •   E erythromycin
       R retrovirals           •   S sertraline               •   C cipro, cimetidine
       A antifungals
       G grapefruit
                                                               •   G grapefruit juice
       E erythromycin
Drugs Withdrawn For Excessive
Adverse Drug Reactions
   Terfenadine (Seldane)—February 1998
   Mibefradil (Posicor)—June 1998
   Astemazole (Hismanol)—July 1999
   Cisapride (Propulsid)—January 2000
   Fluvoxamine (Luvox)—2005
   All relate to P450 enzymatic interactions with
    other drugs

                                       Drug Interactions
                                        (2006)
 Most Dangerous Psychotropic Drug
 Interactions
 Meperidine and phenelzine
   Libby Zion reaction (serotonin syndrome)
 Paroxetine and buspirone
 SSRIs,TCAs, divalproex, metoclopramide,
  sumatriptan, tramadol (Ultram), mirtazapine
  (Remeron)
   Serotonin syndrome
 Lamotrigine (Lamictal) and valproate (Depacon)
   Stevens Johnson syndrome
Overlooked Causes of Drug Toxicity and
Interactions
 P450 enzyme competition (2D6)—inducers,
  inhibitors
 Drug/diet interactions
   Grapefruit juice, tobacco, St. John’s Wort
 Drug/OTC interactions
   Dextromethorphan (Dexedrine) and SSRIs
 Additive side effects
   anticholinergic
   Orthostatic hypotension due to TCAs,
    metoclopramide, BPH medications and
    haloperidol (Haldol)
1.       Organization helps
          Pattern recognition is the key
2.       There are essentially only 3 groups of meds
          (antidepressants, mood stabilizers and
           antispsychotics)
3.       Try to remember what the classes of drugs are
          both the indications and side effects are similar
…Samuel Johnson
   Acknowledgements
   Review Course in
    Psychiatry: Dr.
    Charbonneau
   Dr. Huntington’s 2007
    psychopharm lecture

				
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