Psychopharmacology of Antidepressants, Mood Stabilizers and Anxiolytic/Sedative-Hypnotics

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Psychopharmacology of Antidepressants, Mood
Stabilizers and Anxiolytic/Sedative-Hypnotics

• Philip G. Janicak, M.D.
• Professor of Psychiatry
• Rush University Medical Center

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Objectives

• Characterize the different classes of
  antidepressants and mood stabilizers based on
  their mechanism of action
• Review adverse effects of these agents
• Provide a summary of the pharmacokinetics and
  potential for drug interactions
• Review treatment strategies for the drug
  management of depression and bipolar mania based
  on the existing data, clinical experience, and
  risk-benefit ratio

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Psychopharmacology of Antidepressants and Mood
Stabilizers
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Psychopharmacology of Antidepressants and Mood
Stabilizers
Schematic diagram of Monoamine Neuron
Electron microscope
Fluorescence microscope
Cell body
Amine granules
Axon
Varicosities
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Components of a Synapse
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Major Classes of Antidepressants Defined by
Putative Mechanism of Action

• SE and NE uptake inhibition
• Tricyclic antidepressants (TCAs)
• Venlafaxine
• Duloxetine
• SE uptake inhibition
• Serotonin selective reuptake inhibitors (SSRIs)
• 5-HT2 receptor blockers and SE uptake inhibition
• Nefazodone (phenylpiperazine)
• NE uptake inhibition
• Atomoxetine
• DA and NE uptake inhibition
• Bupropion (aminoketone)
• Monoamine oxidase inhibitors (MAOIs)
• Nonselective and irreversible
• Selective and/or reversible (RIMAs)

Not available
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Pharmacodynamics of Antidepressants

• Norepinephrine receptors
• Postsynaptic (alpha1 and alpha2 beta1 and beta2
• Presynaptic (alpha2)
• Serotonin receptors
• Postsynaptic (5-HT1A and 5-HT2)
• Presynaptic (5-HT1A)
• Others
• Dopamine
• Acetylcholine
• CRH

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Pharmacology of Mirtazapine
de Boer, J Clin Psychiatry, 1996
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Cascade of Intraneuronal Events
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Potential Adverse Effects ofAntidepressant
Therapy
Central Nervous System Dizziness, cognitive
impairment, sedation, light-headedness, somnolence
, nervousness, insomnia, headache,
tremor,changes in satiety and appetite
Cardiac Orthostasis, hypertension, heart
block,tachycardia
Gastrointestinal Nausea, constipation, vomiting,
dyspepsia, diarrhea
Urogenital Erectile dysfunction, ejaculation
disorder, anorgasmia, priapism
Autonomic Nervous System Dry mouth, urinary
retention, blurred vision, sweating
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Antidepressants Drug Interactions

• The pharmacologic action of a drug may be altered
  with the coadministration of a second drug by
• Increasing or decreasing a known effect
• Creating an adverse effect
• Creating a new effect not seen with either drug
  alone
• Interaction may be pharmacodynamic,
  pharmacokinetic or idiosyncratic

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Antidepressants and the Cytochrome P450 System

• Antidepressants and mood stabilizers may be
  inhibitors, inducers or substrates of one or more
  cytochrome P450 isoenzymes
• Knowledge of their P450 profile is useful in
  predicting drug-drug interactions
• When some isoenzymes are absent of inhibited,
  others may offer a secondary metabolic pathway
• P450 1A2, 2C (subfamily), 2D6 and 3A4 are
  especially important to antidepressant metabolism
  and drug-drug interactions

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Minimizing the Risk of Drug Interactions
Associated with Antidepressants

• When adding an antidepressant with a potential
  for pharmacokinetic interaction to another drug,
  clinicians could
• Reduce the dose of the current drug
• Begin with a low dose of the antidepressant
• Use therapeutic drug monitoring where appropriate
• Monitor therapeutic and adverse effects
• Choose an antidepressant with a favorable profile
  for that interaction

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Treatment of an AcuteMajor Depressive Episode
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• Major depressive episode
• mild to moderate
• single or recurrent
• nonpsychotic

• SSRI, VENLAFAXINE, NEFAZODONE, OR MIRTAZAPINE (if
  expense not an issue)
• (or)
• USE PREVIOUSLY EFFECTIVE AD
• (at least 6 weeks with adequate dose and/or
  plasma level)
• (or)
• HCA (if side effects are tolerated preferably a
  secondary amine TCA)

start
Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
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Treatment of an AcuteMajor Depressive Episode
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• Atypical depression

start

• MONOAMINE OXIDASE INHIBITOR (MAOI)
• (N.B. Must wait at least 5 weeks after
  fluoxetine 2-3 weeks after other SSRIs,
  venlafaxine, nefazodone, mirtazapine)

(insufficient response)
Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
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Treatment of an AcuteMajor Depressive Episode
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• Psychotic depression

start

• SECOND GENERATION ANTIPSYCHOTIC (SGA)
• plus AD
• ELECTROCONVULSIVE THERAPY (SGA)
• Possibly TMS or VNS

or
(insufficient response)
may start

• Serious suicidal risk
• Rapid physical deterioration
• Prior history of nonresponse to medication and
  /or good response to ECT

Adapted from Janicak PG, Davis JM, Preskorn SH,
Ayd FJ Jr. Principles and Practice of
Psychopharmacotherapy. 3rd ed. Philadelphia, PA
Lippincott Williams Wilkins 2001.
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Bipolar Disorder Major Points

• Bipolar and related disorders are some of the
  most challenging conditions to diagnose and
  manage
• Pharmacotherapy is the primary treatment
• Lithium is often insufficient
• Anticonvulsants and second generation
  antipsychotics may be effective alternatives or
  supplements

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Bipolar DisorderGeneral Considerations

• Afflicts 1 of the population
• Psychosocial/environmental stressors influence
  occurrence
• Birth cohort effect/genetic risk
• High morbidity and mortality
• Overall, 11 suicide rate
• Untreated, 20-25 will commit suicide

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Mood DisordersTherapeutic Options
Lithium
First generation antipsychotics Second
generation antipsychotics Clozapine Olanzapine Ri
speridone Quetiapine Ziprasidone Aripiprazole
Anticonvulsants Valproate Lamotrigine Carbamazep
ine Oxcarbazepine Topiramate Gabapentin

• Pharmacological/Somatic
• Antidepressants OLZ/FLU
• Electroconvulsive therapy
• Possibly
• Bright light therapy
• Transcranial magnetic stimulation
• Vagal nerve stimulation
• Sleep deprivation

Psychotherapy Cognitive behavioral
therapy Interpersonal therapy Marital/family
counseling Group therapy
FDA approved
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Lithium(Monovalent cation)
ADVANTAGES DISADVANTAGES

• 50 years of clinical experience
• Effective for euphoric mania and hypomania
• Reduces mortality rate, primarily by decreasing
  suicide
• FDA-labeled indication
• Inexpensive

• Narrow therapeutic index
• Slow onset of action
• Less effective for certain subtypes
• Adverse effects
• Teratogenicity
• Tremor
• Polyuria/polydipsia
• Cognitive
• Thyroid

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Lithium
Neurotransmitters NE ? (?) NE/AcH Balance
Hypothesis DA ? (?) 5HT ? (?) Permissive
Hypothesis GABA ? (?) GLU ACH ? (?) NE/AcH
Balance Hypothesis Signal Transduction G-Protein
-PLC ? AC (cAMP) ? (?) 2nd Messenger
Dysbalance Hypothesis Ionositol (IMP) ?
(?) Inositol-Depletion Hypothesis cGMP ?
(?) PKC (?,?) -MARKS ? (?) GSK-3? ? AP-1
(fos,jun) ? (?) -DNA BINDING
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Anticonvulsants

• Valproate
• Lamotrigine
• Carbamazepine
• Gabapentin
• Topiramate
• Tiagabine
• Others

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Valproate(Simple branched-chain carboxylic acids)
ADVANTAGES DISADVANTAGES

• Rapid onset
• Can be used as initial treatment
• High quality of clinical studies
• Effective in bipolar subtypes
• FDA-labeled indication

• Limited long-term data
• Adverse effects
• weight gain
• tremors
• hyperammonemia
• pancreatitis
• hepatotoxicity
• teratogenicity
• PC PCOS (?)

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Lamotrigine
ADVANTAGES DISADVANTAGES

• Effective in bipolar depression, maintenance
• Effective in bipolar rapid cycling
• FDA approved

• Slow titration
• Headache
• Dizziness
• Diarrhea
• Rash

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Anticonvulsants
Neurotransmitters VPA LTG CBZ GBN TOP NE ?
(?) DA ? (?) ? (?) 5HT ? (?) GABA ? (?)
? (?) ? ? GLU ? (?) ? (?) ? (?) ?
(?) Signal Transduction AC ? (?) IMP ?
(?) cGMP ? (?) PKC ? (?) AP-I ? (?)
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Second Generation Antipsychotics

• Olanzapine
• Clozapine
• Risperidone
• Quetiapine
• Ziprasidone
• Aripiprazole

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Olanzapine
ADVANTAGES DISADVANTAGES

• Quality of trials for bipolar mania
• Benefits both mood and psychotic symptoms
• Possibly more rapid onset of action
• Safer during pregnancy (?)
• FDA-labeled indication

• Limited long-term data
• Adverse effects
• Weight gain
• Diabetes / DKA (?)
• EPS

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Second Generation Antipsychotics
Neurotransmitters CLZ RISP OLZ QTP
ZPD ARIP NE ? ? 5-HT ? ? ? ? ?
? DA ? ? ? ? ? ? AcH ? ?
Partial agonist at D2 and 5-HT1A
receptors Antagonist at 5-HT2 receptor
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Pharmacokinetic Properties ofPrimary Mood
Stabilizers
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Mood Stabilizers Drug Interactions

• Lithium
• Renal excretion (e.g., diuretics, NSAIDs)
• Anticonvulsants
• Enzyme induction (e.g., carbamazepine)
• Enzyme inhibition (e.g., valproate)
• Second generation antipsychotics
• Enzyme inhibition (2D6) / induction (1A2)
• Protein binding

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Strategy for Treatment of Acute Mania
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• Mild to moderate symptoms

• Lithium (0.8 - 1.2mEq/L)
• or Valproate (50-125 ug/mL)

start
(insufficient response marked agitation)
Consider loading dose strategy (i.e., 20 to
30 mg/kg/day)
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Strategy for Treatment of Acute Mania
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• WITHDRAW ANTIDEPRESSANT
• if present
• THYROID SUPPLEMENT
• if TSH elevated

(insufficient response)
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Strategy for Treatment of Acute Mania
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• Rapid cycling
• Mixed states
• Organic affective syndrome
• Severe psoriasis
• Prior nonresponse to lithium

may start

• VALPROATE/LAMOTRIGINE
• w/wo
• ANTIPSYCHOTIC/BZD

(insufficient response)
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Strategy for Treatment of Acute Mania
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• CARBAMAZEPINE
• w/wo
• ANTIPSYCHOTIC/BZD

(insufficient response)
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Strategy for Treatment of Acute Mania
Psychopharmacology of Antidepressants and Mood
Stabilizers
Clinical Presentation Treatment Strategy

• Immediate danger
• Previous good response to ECT
• Medical contraindication to pharmacotherapy

• ELECTROCONVULSIVE
• THERAPY (ECT)
• bilateral may be more effective than unilateral,
  nondominant ECT

start
(insufficient response)
ECT plus SGA
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References

• Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr.
  Principles and Practice of Psychopharmacotherapy.
  3rd ed. Philadelphia, PA Lippincott Williams
  Wilkins 2001383-462.
• Janicak PG, Martis B. Strategies for
  treatment-resistant depression. Clinical
  Cornerstone. 19991(4)58-71.
• Janicak PG, Winans E. The use of copharmacy in
  the treatment of acute mania. Directions in
  Psychiatry. 199818 Lesson 1.
• Bowden CL, Janicak PG, Orsulak P, et al.
  Relationship of serum valproate concentrations to
  response in mania. Am J Psychiatry.
  1996153765-770.
• Janicak PG. Antipsychotics and mood disorders A
  complicated alliance. Current Psychiatry.
  20021(1)11-17.

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Abstract

• Mood disorders are some of the most common
  conditions in all of medicine. The consequences
  in terms of morbidity, mortality (especially as
  relates to suicide) and economic impact are
  substantial. For example, it is conservatively
  estimated that total direct and indirect costs
  for depression approach the 44 billion dollar
  level annually in this country. Tragically, the
  majority of patients with mood disorders are
  misdiagnosed, receive inappropriate or inadequate
  treatment or no treatment at all.
• Drug treatments of mood disorders have expanded
  with the recent introduction of several new
  antidepressants and mood stabilizers. Refinement
  in diagnosis and newer therapies will certainly
  improve our ability to treat these conditions.
  Most importantly, a growing understanding of
  mechanisms of action of newer treatments will
  inevitably help to unravel the basis for these
  common debilitating conditions.

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Antidepressants
Oral Dosage Range (mg/day)
CLASS/GENERIC NAMES
TRADE NAME
TRICYCLICS Amitriptyline Elavil 75-300 Imipramine
Tofranil 75-300 Doxepin Sinequan 75-300 Desipra
mine Norpramine 75-300 Nortriptyline Pamelor 75-3
00 Trimipramine Surmontil 75-200 Protriptyline V
ivactil 20-60 Clomipramine Anafranil 100-250
TETRACYCLICS Maprotiline Ludiomil 75-225 Mirtazap
ine Remeron 15-45
SEROTONIN REUPTAKE Fluoxetine Prozac 5-80 INHIBITO
RS Sertraline Zoloft 25-200 Paroxetine Paxil 10-5
0 Fluvoxamine Luvox 100-300 Citalopram Celexa 20
-40 Escitalopram Lexapro 10-20
NOREPINEPHRINE REUPTAKE Reboxetine Vestra 2-4 INH
IBITORS
DIBENZOXAZEPINES Amoxapine Ascendin 200-600
TRIAZOLOPYRIDINES Trazodone Desyrel 150-600 Nefaz
odone Serzone 100-600
AMINOKETONES Bupropion Wellbutrin 300-450
PHEYLETHYLAMINES Venlafaxine Effexor 75-375
TRIAZOLOBENZODIAZEPINES Alprazolam Xanax 1-4.5
MONOAMINE OXIDASE Isocarboxazid Marplan 10-30 INHI
BITORS Phenelzine Nardil 15-90 Tranylcypromine P
arnate 30-60
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Not Available in US
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Adverse Effects of Antidepressants
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Adverse Effects of Antidepressants (cont)
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Comparison ofPharmacokinetic Parameters
Citalopram Fluoxetine Sertraline Paroxetine Fl
uvoxamine
protein bound 80 94 99 95 77 Peak plasma level
(hour) 3-4 6-8 6-8 2-8 2-8 Half-life
(hours) 35 24-72 25 20 15 Dose range
(mg/d) 20-60 20-80 50-200 10-50 50-300 Absorption
altered by fast or fed status No No Yes No No Lin
ear pharmacokinetics Yes No Yes No No GI
absorption () 100 80 44 64 94
Van Harten. Clin Pharmacokinet, 1993. Preskorn.
Clin Pharmacokinet, 1997. Data on file, Forest
Laboratories, Inc. Preskorn. J Clin Psychiatry,
1993.