T. Lau, MD, FRCPC, MSc., Assistant Professor, UNIVERSITY OF OTTAWA

ObjectivesTo 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

To review drug interactions and serious adverse drug reactions

Geriatrics, Royal Ottawa Mental Health Centre

“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 medications2. Pathways and actions of biogenic amine

neurotransmitters3. 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 Psychopharmacology2. Some Principles of Pharmacology3. Neurons & Neurotransmitters

Psychopharmacology

MAOI

SNRISSRITCA

Mono-amine oxidase inhibitor

Noradrenergic and specific serotonergic

antidepressant

Non-selective tricyclic AD

Selective serotonin re-uptake inhibitor

Serotonin noradrenaline re-uptake inhibitors

NaSSA

1950 1960 1970 1980 1990 200I

AAPAP

Atypical Antipsychotic

•Antidepressants•TCAs (tertiary, secondary)•MAOIs/RIMAs•SSRIs•SNRIs•SARI•DRI

•Mood stabilizers•Lithium•Anticonvulsants•Atypical APs

Antipsychotics “major

tranquilizers” Typical (1st

generation) Atypical (2nd

generation) Sedative/

hypnotics “minor

tranquilizers” Benzos barbiturates

Cognitive Enhancers 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 brain1. Mesocortical2. 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 Diagnosis1. Mood disorders2. Anxiety3. Psychosis

• Treatment Algorithms1. Depression2. Bipolar Disorder3. Schizophrenia

• 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 Mood disorders

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 dosagesR/A Diagnosis. Optimize

dose

Inadequate response

Switch to new antidepressant from a different

class

Augment 1st Lithium2nd atypical

antipsychotic3rd Lamotrigine4th Thyroid T3

Combine 2 antidepressants from different

classes

Consider ECT at any time particularly when

Very severe depressionNot eating or drinking

CatatoniaPsychosis

Suicide RiskMed Intolerance / Pregnancy

Consider psychotherapy at any point particularly with

early childhood trauma

Determine Phase of illness

MANIA DEPRESSION

LithiumEpival

Typical and Atypical

AntipsychoticsECT

1) Lithium (for Cade’s disease)2) Mood Stabilizer (Li, VPA, AAP) plus Antidepressant3) Lamotrigine4) Seroquel Monotherapy5) ECT

LithiumAAP

?Lamictal

Consider ECT at any time particularly when

Very severe depression or uncontrolled maniaNot eating or drinking

CatatoniaPsychosis

Suicide RiskMed Intolerance / Pregnancy

EUTHYMIAMIXED

AAPCMZP

APA Schizophrenia Guidelines 2004. Schizophrenia Tx Algorithm

Schizophrenia Tx Algorithm

Antidepressants SSRI’s SNRI’s SARI’s NaSSA’s NDRI TCA’s MAOI RIMA’s Novel Agents

Mood stabilizers Lithium Epival Lamotrigine

Antipsychotics Clozapine Olanzapine Risperidone Quetiapine Ziprasidone

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 autoreceptorsReturn 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 2autoreceptorsReturn of normal firing rate with ongoing decreased reuptake.

Increased NE release and neurotransmissionDownregulation of beta adrenergic receptorsSensitization 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 H H/A’s 20-30% E Euphoria 8% MDD, 50% BAD N Nervousness (agitation, dizziness,

restlessness) E Endocrine (SIADH, galactorrhea) W weight gain A anorgasmia and other sex problems

20-50%) G GI upset, GI bleed (age>85, prev GI

bleed) E Excretions S Sleep disturbance (REM suppression

except luvox, inc awakenings, nocturnal myoclonus), sedation

75% tolerate SSRI’s w no ASE’s 25% ASE disappear by day 14 (most w/I 3-4d).

~10% do not develop tolerance 5HT syndrome, discontinuation syndrome

GASH: •GI (upset, N/D/C, bleed 1:8000)•Activation / Anxiety, •Sexual dysfxn / Sleep disturbance / Sedation / Seizure 0.2%, •Head ache

In the elderly, >85 or previous GI bleed increased risk of GI bleed [Dalton CNS Drugs 2006]. Retrospective data base reviews limited by confounders including NSAID use.

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 monoamines, depending on the dose (Harvey AGP 2000)

At low doses 5HT (same ASE’s: nausea, agitation,

sexual dysfxn, insomnia) At medium to high both 5HT and

NE Reuptake blockade Watch for HTN, severe insomnia,

agitation, nausea, H/A, EPS At very high doses all three

May be useful in melancholic, severely depressed inpatients and those refractory to other antidepressants

Steady state [ ] ~3d, t ½ ~5hrs, ~11h for active metabolite (ODV ~56% of any given dose), unless XR.

Metabolized by 2D6, weak inhibitor of 2D6

Few drug interactions May be safer if combined with

coumadin Mirtazapine or Nefazadone may

block some 5HT effects ASE’s (E vs placebo)

[ISDNSSH]: Insomnia(18vs10%),

somnolence 17-23 vs. 8-9%), dizziness (19vs 8%), anxiety (XR better), dry mouth (22 vs 11%, 12 vs. 6% XR), nausea (31-37 vs. 11-12%), h/a (24% comparable to placebo), sweating (<75: 5-6% =placebo, 225: 12.4%, 375 19.3%), sexual dysfxn (12-16 vs <1%), sustained HTN (<75: 1%=placebo, 225: 2.2, 375: 4.5%), withdrawal effects common

Desvenlafaxine (Pristiq) AKA, O-desmethylvenlafaxine,

Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine (Effexor)

It is being targeted as the first non-hormonal based treatment for menopause.

Theoretically useful for slow 2D6 metabolizers

The most commonly observed ASE (incidence >= 5% and at least twice the rate of placebo in the 50 or 100 mg dose groups) were nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, priapism, night terrors, anxiety, and delayed ejaculation.

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 L lowers seizure threshold

seizures 0.1% < 300 mg/d, 0.4% > 400 mg/d P p450 interactions I insomnia*, irritability* N nausea* G GI distress A agitation, amphetamine like

effects, allergic reactions C constipation, cardiac

palpitations T tremor, tinnitus

Recommended dose 150-300 mg/d single SR dose. Start at 100 and titrate upwards to clinical effect. T1/2 = 10-14h/SR 21h, Time to peak plasma [ ] =2-3h, Steady state levels b/o 3 metabolites = ~10 days.

Inhibitor of 2D6, substrate of 2B6, has three active metabolites

NDRI (low NA, high DA, also some 5HT, alpha 2, M1)

Labs may give false positive urine amphetamines

Tertiary Amines Imipramine, Amitriptyline,

Doxepin, Clomipramine Secondary Amines

Desipramine, Nortriptyline, Protriptyline

Tetracyclics Amoxapine Maprotiline

CYP 1A2

CYP 2D6

CH3

Relatively 5HT>NE

More other receptors

ASEs

NE>5HTFewer side

effects

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

MAO – oxidative deamination of amines 5HT, NE, DA

Discovered accidently in tx of TB (IPZ)

MAOIs structurally similar to catecholamines

MAOIs block monoamine oxidase inhibitor permanently and irreversibly

Suggested to be more effective in MDD with atypical features

Divided into 2 groups Hydrazine (Phenelzine-

Nardil) and Non-Hydrazine (Tranylcypromine-Parnate)

Nardil-more sedating Parnate-amphetamine like

qualities, can be activating

Common ASEs Orthostatic hypotension Weight gain Sexual dysfunction Ankle edema

Other Side Effects Insomnia with daytime sedation

‘Nardil Nod’ Myoclonus, tremor and akathisia,

parathesias Dry mouth and urinary retention

Rare but serious Hypertensive crisis (tyramine

cheese reaction-displaces NE in vesicles). Guidelines is <6 mg

Blood dyscrasias 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

LithiumEpivalLamotragineCarbamazepineGabapentin (more used for anxiety or neuropathic pain)

Simplest solid element Natural salt discovered

in 1817 First described by John

Cade (1949) to have antimanic properties

Pharmacokinetics 100% absorbed, 0%

protein bound T ½=24-36 hrs No metabolites 100% renal excretion with

renal excretion interactions

Pharmacology Increases release of 5HT Blocks release of NE and

DA Blocks receptor

mediated actions of several hormones on adenylate cyclase (eg. ADH and TSH)

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)

T Tremor H Hypothyroid E CG changes M uscle weakness A lopecia G I upset I ncreased WBC

(transient) C ardiac arrhythmias W eight gain A cne N eurological D rinks/ diabetes

insipidus GPWITH (GI, Polys, wt gain, incr

WBC, tremor, hypothyroid)

Levels Increased by NSAIDS, thiazide diuretics,

ACEI, tetracycline, anticonvulsants Also consider decreased clearance with

aging, renal disease, dehydration, low salt diet

Decreased by osmotic diuretics (eg. mannitol), carbonic anhydrase inhibitors, caffeine, theophylline, high salt diet

Pregnancy (increased plasma volume but also GFR).

ASE’s Poly’s (60%), N, abdo pain, V, D, vertigo,

muscle weakness, fine tremor M>F 54 vs. 26%, wt gain F>M (47 vs 18%), hypothyroidism (5-15% F>M (recent study 37 vs. 9% F>M, predictor=wt gain).

Toxicity: usually starts w GI then tremor, then thirst and inc u/o, then drowsiness, ataxia, tinnitis, blurred vision.

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%) O oligomenorrhea / PCO

(menstral irreg in 45%) B blood dyscrasia

(thrombocytopenia, anemia) A alopecia L LFT elevation (up to 44%) D dysarthria & F fat (59% mean wt gain 8-

21 kg F>M), (also overestimates serum FFA)

A ammonia levels can rise T teratogen (5-15%)

Common ASE: N, V, indigestion, usually transient and rarely require d/c. 11% discontinuation rate in trials.

Common: [WITH GST] Wt gain, Irregular menses, Teratogen, Hair loss, GI, Sedation (cognitive

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%), ataxiaS 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• Phenothiazine antipsychotics

• Chlorpromazine, Fluphenazine, Mesoridazine, Perphenazine, Prochlorperazine, Promazine, Thioridazine, Trifluoperazine

• Thioxanthene  • Thiothixene [Navane]

• Dibenzodiazepines • Loxapine (Loxitane) Clozapine

(Clozaril)• Butyrophenones

• Droperidol (Inapsine) Haloperidol (Haldol)

• Indolone • Molindone (Moban)

• Diphenylbutylpiperidine • Pimozide (Orap)

ATYPICALS• Amisulpride,

Aripiprazole, Clozapine, Olanzapine, Quetiapine, Risperidone/Paliperidone}, Sertindole, Sulpiride, Ziprasidone, Zotepine

 

More Extrapyramidal symptomsFew side effects on circulatory system. 

D2 blocking action is strong.

High potency group

Low potency group

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

chlorpromazinethioridazine  

haloperidolButyrophenones

Phenothiazines fluphenazine

perphenazine

Phenothiazines

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 medicationAdverse Side EffectsSerotonin SyndromeMechanisms Underlying Drug LevelsDrug 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

Sexual dysfunctionActivating side effects

Insomnia5HT2

Stimulation

`

Psychomotor activationPsychosis

DA reuptakeinhibition

Nausea5-HT3

Stimulation

GI disturbancesActivating effects

5-HT reuptakeinhibition

Dry mouthUrinary retentionActivating effects

Tremor

NE reuptakeinhibition

Postural hypotensionDizziness

Reflex tachycardia

Alpha2 blockPriapism

Alpha1 block

Blurred visionDry mouth

ConstipationSinus tachycardiaUrinary retention

Memory dysfunction

Ach block

Sedation/DrowsinessWeight gain

H1 block

Adapted from Richelson E. Current Psychiatric Therapy. 1993;232-239

Antidepressant

Anticholinergics

Red as a beet VasodilationDry as a bone Dry mucous mbs, anhydrosisHot as a hare HyperthermiaMad as a hatter Delirium, hallucinations, agitation, cognitive

impairmentBlind as a bat Blurred vision, worsens glaucoma, photophobiaBowel and ConstipationBladder 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

1960—tryptophan and MAOIs 1984—Libby Zion: meperidine,

phenelzine and cocaine 15% incidence in patients

overdosing SSRIs Toxic exposure surveillance

system 2002 in the US 7,349 patients reported in 2002 93 deaths 0.4 cases/1,000 patients—

months on SSRIs Oates JA (1960), Neurology

10:1076-1078; Asch DA (1988), N Engl J Med 318(12):771-775

PATHOPHYSIOLOGY Stimulation of 5-HT

receptors in brain, GI tract and vessels

Drugs may stimulate receptors directly Tryptophan Sumatriptan (Imitrek) Buspirone (Buspar)

or block reuptake and metabolism SSRIs Meperidine 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

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)

Boyer NEJM 2005

SEVERE SS combos Phenelzine and

meperidine Phenelzine and SSRIs Paroxetine and

buspirone Linezolide and

citalopram Tramadol and

venlafaxine and mirtazapine

Serotonin Syndrome Agitation/restlessness

(most common) Confusion Hyperthermia Tachycardia, HTN Autonomic instability Diaphoresis Hyperreflexia Myoclonus Ataxia Incoordination

Serious complications Sz, DIC, respiratory

failure, inc temp, death

NMS Fever, rigidity, neuroleptic use + Altered mental status Seizures, coma, catatonia Mutism Dyphagia Leukocytosis Elevated CPK Myoglobinuria Decreased renal fxn Dec TIBC (?epiphen)

Risk factors Underlying medical illness,

young, M, recent dose inc, low TIBC, dehydration, Lithium,

Tx D/C neuroleptic, supportive

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 peripheral, central

sedation, falls / #’s CVS

QTC and conduction defects / repolarization delays

Highest w Thioridazine, Ziprasadone, Haldol (intermediate). K rectifier pump. QTC>480 ms. F>M. Elderly [>75] QTC >430 ms RR of death 2.4 Nilsson Eurospace 2006

orthostatic hypotension, tachycardia

EPS parkinsonism, dystonia,

akathisia, catatonia, NMS Movement disorders. TD NMS

Sexual dysfxn CPZ, thioridazine,

risperidone Seizures

Higher w low potency agents

Miscellaneous 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 increase risk

Polypharmacy Lack of awareness

of cytochrome (CYP) 450 system is a problem.

Most clinically significant interactions have been mediated through P 450

Brown CS (2000), US Pharmacist.

P450 Enzyme System Located in liver, kidney, intestine,

lungs, brain Individual enzymes metabolizing

>95% of all drugs: Subtypes:1A2, 2B6, 2C9, 2C19, 2D6,

3A4

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/drugreactions/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%) SUBSTRATES

B benzos E effexor S sertraline T tertiary amine,

trazadone C clozaril L luvox O OCP N Nefazadone E Erythromycin

INHIBITORS N nefazadone,

norfluoxetine F fluoxetine L luvox

R retrovirals A antifungals G grapefruit E erythromycin

• 2D6 (20-25%)• SUBSTRATES

• E effexor• A AP’s,

antiarrhythmics• T trazadone• C clozaril, codeine• R risperidone• O olanzapine• P prozac, paxil• S secondary amines

• INHIBITORS

• P2 paxil, prozac• B buproprion• S sertraline

• 1A2 (10-15%)• SUBSTRATES

• C clozaril, coumadin, caffeine

• H haldol• A acetaminophen• T tertiary amines,

theophyline• INHIBITORS

• L luvox

• E erythromycin• C cipro, cimetidine• G grapefruit juice

Drugs Withdrawn For ExcessiveAdverse 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