GAD Talk

1
Clinical Psychopharmacology Introduction Assoc
. Prof. Sean Hood Consultant Psychiatrist
Associate Professor in Clinical
Psychopharmacology (UWA) Chair WA Psychotropic
Drug Committee (WAPDC)
2
What this lecture is NOT!
3
What this lecture is NOT!

• NOT a replacement for undergraduate pharmacology
  lectures (rather, a supplement).
• NOT all you need to know (cram!) to pass the
  exam(s).
• NOT a substitute for practical experience.
• NOT the Gold Standard of Psychopharmacology
  Practice.
• NOT a substitute for reading the original
  guidelines (qv)..

4
Slice n Dice
5
Slice n DiceClinical Context
6
Clinical Psychopharmacology Clinical wisdom
informs therapy.
7
This will be hard to grasp without a clinical
context (so come back to these notes later!)
8
Slice n DiceDrugs By Disorder
9
Drugs By Disorder

• Mood Disorders
• Schizophrenia
• Anxiety Disorders
• Substance Abuse
• Personality Disorders
• Organic Mental Disorders
• Somatisation

PBL
10
Slice n DiceDrugs By Neurotransmitter
11
Drugs By Neurotransmitter
12
Drugs By Neurotransmitter

• Monoamine
• Serotonergic
• Noradrenergic
• Dopaminergic
• GABA
• Benzodiazepines
• Hypnotics
• Mood Stablisers

• Acetylcholine
• Glutamate
• Histamine
• Neuropeptides
• CCK
• CRF, Vasopressin
• NPY
• NK
• NPS
• Galanin
• Oxytocin

13
(No Transcript)
14
(No Transcript)
15
(No Transcript)
16
Neurotransmission The Process
17
Neurotransmission Drug Action
18
Slice n DiceDrugs By Disorder Drug Class
19
A Rough Guide to AntidepressantsBy Drug Class
20
A Rough Guide to AntidepressantsBy Drug Class

• Antidepressant Efficacy
• Essentially little difference
• ECT gt MAOIs gt SNRIs gt SSRIs TCADs
• Factors Influencing Drug Choice
• Previous response
• Allergies
• Concurrent medical illness
• Concurrent psychiatric illness
• Side effect profile
• Interaction potential
• (mainly through Cytochrome p450 interactions)
• Toxicity in overdose - suicidality

21
A Rough Guide to AntidepressantsBy Drug Class

• SSRI Common Side Effects
• Insomnia, headache
• Nausea, anorexia
• Diarrhea
• Constipation
• Sexual dysfunction
• Decreased libido
• Anorgasmia
• Nervousness, tremor
• Myoclonus
• Teeth-clenching

22
A Rough Guide to AntidepressantsBy Drug Class

• SSRIs Compared
• Fluoxetine
• Long t ½
• Activating (esp. atypical depression)
• BPAD depression ( Olanzapine)
• Diabetes
• Sertraline
• CVS
• Some ? DA at high doses, good for atypical
  depression, does not elevate PRL.

23
A Rough Guide to AntidepressantsBy Drug Class

• SSRIs Compared cont.
• Fluvoxamine
• Low incidence sexual SE (in this class)
• Sedating, use for anxious depression, OCD.
• (es) Citalopram
• Most serotonergic, well tollerated, least CYP450
  interactions, allosteric site augment
• Depression anxiety, may suffer from sanguine
  poop-out
• Paroxetine
• Category D Pregnancy, discontinuation syndrome
  (Panorama, Seroxat).
• Weak antimuscarinic (? constipation, dry mouth,
  sedation), ? Most potent anti-anxiety

24
A Rough Guide to AntidepressantsBy Drug Class

• NASSA (Mirtazepine)
• Daughter of mianserin
• Histaminergic (? sedation, weight gain)
• NA at higher doses (paradoxical activation)
• 5HT2,3 antagonism ((N) sleep, sex, nausea)
• California Rocket Fuel ( Venlafaxine)
• NARI
• Venlafaxine
• Side Efexor nausea, hypertension, W/D
• 225 mg NA, 350 mg DA
• Rx refractory, neuropathic pain, fibromyalgia
• Duloxetine
• Single dose (60 mg), utility in somatic pain.
  GAD, DPNP
• Sleep disturbance. Nausea if taken on empty
  stomach
• RIMA (moclobemide)
• no effects, no side effects
• Comorbid BPAD I-III, reserve for specialist use.

25

• Significant Debate
• AMI vs AD NNT42
• AMI vs SSRI NNT 34.5
• But 5-6 suffer Ad. Ev.
• Not useful in SAnD, but (imipramine) useful in
  Panic Disorder.
• a1 NA, H, Chol profile well known.
• Overdose safety

26
A Rough Guide to AntidepressantsBy Drug Class

• TCAD Common Side Effects
• Weight gain
• Anticholinergic
• Dry mouth, cavities
• Blurred vision
• constipation
• Urinary retention
• Tachycardia
• Sedation, fatigue
• Tremor, dizziness
• Impotence
• Extremely dangerous in overdose

27
A Rough Guide to Antimanic AgentsBy Drug Class

• Lithium
• Efficacy
• Long term Rx ? suicide ( 7x)
• N1594, Median duration of continuous use of Li
  after it was first prescribed was 76
  days(Johnson and McFarland 1998)
• Discontinuation ? ? rate suicide (20x in 1st
  yr)(Baldessarini et al 1999)
• Side Effects
• Acute
• nausea, vomiting, diarrhoea, urinary frequency,
  dry mouth, tremor, muscle weakness
• Long-term
• weight gain, sexual dysfunction,
  hypothyroidism(low T3 and T4 with high TSH)
• nephrogenic diabetes insipidus-caused by failure
  of AVP to act on the distal tubule
• increases risk of tardive dyskinesia
• Lithium toxicity
• drowsiness, ataxia, slurred speech, tremor,
  confusion, convulsions

28
A Rough Guide to Antimanic AgentsBy Drug Class

• Valproic Acid (Valproate)
• Well tolerated as long term therapy
• Occasional tremor, weight gain, alopecia
• Nausea, reduced platelet and white cell count,
  abN LFTs
• Less toxic than lithium and carbamazepine
• Some teratogenicity
• Rapid Cycling drug of choice
• Carbamazepine
• Adverse effects
• CNS headache, drowsiness, diplopia
• Liver elevation of ?GT, hepatitis, cholestatic
  jaundice
• Other GI nausea, vomiting(anticholinergic)
• Blood dyscrasias
• Skin rashes
• Teratogenic effects folate deficiency?

29
Consider Valproic Acid for Rapid Cyclers
30
A Rough Guide to Antimanic AgentsBy Drug Class

• Lamotrigine
• Useful Rx for Bipolar Depression (non-manic
  inducing)
• No effects on folate levels (ct other
  anticonvulsants)
• S/E dizziness, headaches, tremor,nausea, rash
  (10)
• Gabapentin
• GABA analogue, but acts on a2d subunit of the
  voltage-dependent calcium channel in the CNS
• Also used in neuropathic pain
• S/E dizziness, drowsiness, and peripheral oedema
• Pregabalin
• GABA analogue, but acts on a2d subunit of the
  voltage-dependent calcium channel in the CNS
• Used also in Neuropathic pain, GAD
• S/E dizziness, drowsiness esp.

31
(No Transcript)
32
(No Transcript)
33
A Rough Guide to Anxiolytics
34
A Rough Guide to Anxiolytics

• SSRIs
• First line agents in Panic, Social Anxiety, OCD,
  GAD, PTSD.
• Doses Caveats
• Panic start 1/2 , go 2x
• SAnD go 1.5x (NO TCAD, ETOH, Beta Blocker)
• OCD go 3x (/- atypical antipsychotic)
• PSTD ?
• GAD ( Venlafaxine, Buspirone)
• BZDs
• Higher doses, Higher Frequency dosing (Receptor
  shift)
• Alprazolam (Xanax) v. potent anxiolytic but
  addictive.
• Clonazepam best evidence base (.5 ? 8 mg /day)
• Hypnotics
• Z drugs
• Zolpidem !
• Psychological Rxs
• CBT As effective as medications
• ExRP, (EMDR) for PTSD

35
A Rough Guide to Anxiolytics

• Benzodiazepines
• Contraindications
• Severe respiratory depression
• Severe hepatic impairment
• Myasthenia gravis
• Side Effects
• Behavioral Disinhibition
• hostility, aggressiveness, rage reactions
• paroxysmal excitement, irritability
• Psychomotor Impairment
• synergistic effects with ETOH, dysarthria,
  ataxia, drowsiness
• Cognitive Impairment
• impaired visuospatial ability sustained
  attention tasks
• Withdrawal Phenomena
• flu-like symptoms (mild), psychotic s(x)s or
  seizures (severe)

36
(No Transcript)
37
A Rough Guide to Antipsychotics By Drug Class

• Typical Antipsychotics
• Out of favour. Why?
• Phase I Low Potency (Chlorpromazine)
• Phase II High Potency (Haloperidol)
• Atypicals
• Clozapine ( atypicality / agranulocytosis)
• Olanzapine ( metabolic syndrome)
• Risperidone ( postural hypotension / EPSE)
• Quetiepine ( sedation)
• Aripiprazole ( partial agonism)
• Amisulpiride ( non-5HT atypicality)
• Ziprasidone ( new)
• Issues
• EPSE
• QTc prolongation
• Weight gain metabolic syndrome
• Depots

38
(No Transcript)
39
(No Transcript)
40
Serious Side Effects
41
Serious Side Effects

• Activation Syndrome (Jitteriness)
• Discontinuation Syndrome (Withdrawal)
• Serotonin Syndrome (5HT Syndrome)
• Extrapyramidal Side Effects (EPSE)
• Neuroleptic Malignant Syndrome (NMS)
• Pregnancy Issues

42
Serious Side Effects Activation Syndrome
(Jitteriness)

• Early anxiety, agitation, irritability 4-65
• JAS is inconsistently defined.
• No robust evidence that the incidence differed
  between SSRIs and TCAs, that there was a higher
  incidence in anxiety disorders, or whether the
  emergence of JAS had a predictive value on the
  response to treatment.
• JAS appears to be a separate syndrome from
  akathisia (qv).

43
Sinclair, Davies, Hood et al. The
antidepressant-induced jitteriness / anxiety
syndrome JAS. A systematic review. British
Journal of Psychiatry (in press).
44
Serious Side Effects Discontinuation Syndrome
(Withdrawal)

• Can occur during or following the interruption,
  lowering of dose or discontinuation of SRI drug
• T ½ of drug (24 hrs 1 week)
• Sx Dizziness,Sleep Disturbance,Tremor, Anxiety,
  Nausea, Sweating, Mood Lability
• Sx electric shocks, post-SSRI sexual
  dysfunction
• Avoid by low dose, taper, fluoxetine cross taper
• Esp paroxetine, venlafaxine, duloxetine

45
Serious Side Effects Serotonin Syndrome

• Excess Serotonin (iatrogenic, overdosage)
• Clinical Triad
• Cognitive effects
• mental confusion, hypomania, hallucinations,
  agitation, headache, coma.
• Autonomic effects
• shivering, sweating, fever, hypertension,
  tachycardia, nausea, diarrhoea.
• Somatic effects
• myoclonus/clonus (muscle twitching),
  hyperreflexia, tremor.
• Mx
• Supportive, discontinuation

46
EPSE
47
EPSE

• Acute EPSE(first dose chronic Rx)
• Acute Dystonia
• abnormal posturing, especially on movement,
  which may be painful
• Eg oculogyric crisis, torticollis, oromandibular
• Rx anticholinergics (eg benztropine)
• Acute Dyskinesia
• repetitive, involuntary hyperkinetic movements,
  often found in the face and mouth region.
  Writhing, choreoathetoid movements can also be
  found in limbs and trunk. Impaired movements of
  the fingers may appear as though the patient is
  playing an invisible guitar or piano.
• Eg wormlike tongue movements, lip smacking and
  eye blinking
• Rx high potency BZD,
• Acute Akathisia
• (inner) restlessness, with internal gt external
  intensity
• Eg pacing / anxiety / pain / dysphoric
  restlessness
• Rx benztropine, beta-blockers, BZDs
• Parkinsonism
• tremor, hypokinesia, rigidity, and postural
  instability.
• Tardive EPSE(gt 3/12 Rx)
• Tardive Dyskinesia
• Rx prevention, BZD, clozapine ?, vitamin E ?
• Tardive Dystonia

48
Atypicality

• Core Features
• Low EPSE
• Efficacy in positive negative Sx
• Pharmacological selectivity
• 5HT2 gt D2
• Selective D2/D3 blockade
• Low D2 affinity / partial agonism

49
Atypicality
50
Serious Side Effects Neuroleptic Malignant
Syndrome (NMS)

• Commonly confused with Serotonin Syndrome,
  life-threatening (10-15)
• Cause decreased levels of DOPAMINE
  (antipsychotics, genetic)
• Symptoms
• F ever
• E encephalopathy
• V itals unstable
• E levated enzymes (CK)
• R igidity of muscles
• Mx emergency care
• Ct 5HT Syndrome fever, muscle rigidity, CK

51
Serious Side Effects Pregnancy Issues

• TCAs and SSRIs relatively safe
• SSRIs cross the placenta and have the potential
  to affect newborns.
• Although SSRIs have not been associated with
  congenital malformations, some evidence suggests
  that they are associated with neonatal
  complications such as neonatal abstinence
  syndrome (NAS) and persistent pulmonary
  hypertension (PPH)

52
Slice n DiceEstablished Clinical Guidelines
53

• WAPDC
• Guidelines
• http//www.watag.org.au

54
(No Transcript)
55
http//www.ipap.org
56
(No Transcript)
57
(No Transcript)
58
Drug Interactions
59

• http//www.sciencedirect.com/science/journal/1476
  1793

60

• http//www.sciencedirect.com/science/journal/1357
  3039

61
(No Transcript)
62
RANZCP Content

• Topics of RANZCP Guidelines
• anorexia nervosa
• bipolar disorder
• deliberate self harm (youth and adult)
• depression
• panic disorder and agoraphobia
• schizophrenia.
• Types of RANZCP Guidelines
• Clinician (summary full)
• Consumer

63
(No Transcript)