Palazidou 03
-
Upload
henkpar -
Category
Health & Medicine
-
view
583 -
download
0
Transcript of Palazidou 03
Dr Eleni Palazidou MD, PhD, MRCP, FRCPSYCH
1. Fawcett J, Barkin RL. J Clin Psychiatry. 1997; 58(Suppl 6): 32–39. 2. O'Reardon JP, Amsterdam JD. Psychiatr Ann 1998; 28: 633–640.
Approximately 2/3 of patients treated for depression will fail to achieve remission (HAM-D ≤ 7)2
1. Paykel ES, et al. Psychol Med 1995; 25: 1171–1180.
Patients were interviewed at 3-monthly intervals according to the Clinical Interview for Depression and HAM-D17 Rating Scale
Depressed patients with unresolved symptoms are 3 times more likely to relapse1
Kupfer DJ. J Clin Psychiatry 1991;52 (5, Suppl): 28–34.
1. Acute TreatmentFirst 6-12 weeks of treatment - aims at remission (control of
symptoms). Inadequate response is associated with poor prognosis.
2. Continuation Treatment 6 months after full symptom control - to maintain remission
status and relapse prevention.
3. Maintenance TreatmentAims at prevention of recurrence of a further episode of
depression. Indicated when higher risk of these recurrence.
“maintenance dose”
Treatment aimsComplete symptom resolution
Return to premorbid functioning (psychosocial, occupational)
The maintenance of normality
The prevention of recurrence
Limbic SystemLimbic System
PrefrontalPrefrontalCortexCortex LocusLocus
CoeruleusCoeruleus(NA source)(NA source)
Raphe NucleiRaphe Nuclei(5-HT source)(5-HT source)
AmygdalaAmygdala
HippocampusHippocampus
Cooper JR, et al. The Biochemical Basis of Neuropharmacology. 8th ed. New York: Oxford University Press; 2003.
Descending 5-HT pathways
DescendingNA pathways
Normal situation Depression
Monoamine oxidase inhibitors -non-selective, non-reversible (MAOIs)
-selective, reversible (RIMAs)
Monoamine re-uptake inhibitors -non-selective NA & 5-HT (TCAs)
-selective NA & 5-HT (SNRIs) -selective 5-HT (SSRIs) -selective NA (NARIs)
Receptor selective antagonists -alpha2 receptor antagonists –
mianserin, mirtazapine -5-HT2 receptor antagonists - trazodone
ACUTE MECHANISM OF ACTION
UNDESIRABLE PHARMACOLOGICAL
ACTIONS
TCAs Anticholinergic; antihistaminic; alpha1
adrenoceptor blockade;direct membrane
stabilisation
SSRIsCitalopram(Cipromil), Fluoxetine (Prozac),
Fluvoxamine(Faverin), Paroxetine(Seroxat),
Sertraline (Lustral)
5-HT re uptake inhibition
MAOIsPhenelzine(Nardil),
Isocarboxazid(Marplan) Tranylcypromine(Parnate)
Inhibition of MAO-A andMAO-B isoenzymes
Interaction with tyramine and sympathomimetic drugs;
Irreversible and non-selective inhibition of MAO
isoenzymes
RIMAsMoclobemide(Manerix)
Reversible Inhibition of MAO-A
SNRIsVenlafaxine(Efexor)
Duloxetine(Cymbalta)
5-HT and NA re uptake inhibition
Reboxetine(Edronax) NA re uptake inhibition
Mirtazapine(Zispin) Alpha2 adrenoceptor blockade
5-HT2 receptor blockade
Normal situation Depression
Side effectsSide effects ↑↑Weight, sexual dysfunction, Weight, sexual dysfunction, dry mouth, headachedry mouth, headache
Safety in overdoseSafety in overdose Lethal (hypertensive crisis, Lethal (hypertensive crisis, stroke,MI)stroke,MI)
Sympathomimetics Sympathomimetics ¢¢
Tyramine foodstuffsTyramine foodstuffs ¢¢Carbamazepine Carbamazepine ¢¢
Hypertensive crisisHypertensive crisis
ββ-blockers-blockers ↑↑hypotension,bradycardiahypotension,bradycardia
Oral hypoglycaemicsOral hypoglycaemics ↑↑hypoglycaemic effecthypoglycaemic effect
SSRIs SSRIs ¢¢ Nefazodone Nefazodone Serotonin SyndromeSerotonin Syndrome
Bupropion Bupropion ¢¢ Hypertensive crisis, seizuresHypertensive crisis, seizures
Clomipramine Clomipramine ¢¢
SIDE EFFECT PROFILE OF TRICYCLIC ANTIDEPRESSANTS
AnticholinergicDry mouth,
Blurred visionUrinary hesitancy (urinary retention)
ConstipationMemory impairment
Aggravation of narrow angle glaucomaAntihistaminic
SedationWeight gain
Alpha1 adrenoceptor antagonismOrthostatic hypotension
Cardiac effectsCardiovascular effects
Sinus tachycardiaArrhythmias
Conduction delaySudden death
Other side effectsSexual dysfunction
Impaired cognitive and psychomotor skillsConvulsions
SIDE EFFECT PROFILE OF SSRIs
Nausea/vomiting* Abdominal pain
Dry mouthConstipation/diarrhoea
Headache*AstheniaDizziness
Insomnia/somnolenceSweating*Anorexia
Weight lossNervousness/agitation
TremorConvulsions
Dystonic reactionsSexual dysfunction*
(reduced libido, anorgasmia)
Serotonin Syndrome – Suggested Diagnostic Criteria
Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen,
at least three of the following clinical features are present:mental status changes (confusion, hypomania)
agitationmyoclonus
hyperreflexiadiaphoresis
shiveringtremor
diarrhoeaincoordination
feverOther aetiologies (e.g. infectious, metabolic, substance abuse or withdrawal)
have been ruled out.A neuroleptic had not been started or increased in dosage prior to
the onset of the signs and symptoms listed above.
DISCONTINUATION DISCONTINUATION SYNDROMESYNDROME
Dizziness *Dizziness *Electric shock sensations *Electric shock sensations *Anxiety/agitationAnxiety/agitation٭٭InsomniaInsomniaFlu-like symptomsFlu-like symptomsDiarrhoea/abdominal spasmsDiarrhoea/abdominal spasmsParaesthesia *Paraesthesia *Mood swingsMood swingsNauseaNauseaLow moodLow mood
Pharmacokinetic – cytochrome p450
Pharmacodynamic – MAOIs + SSRIs (serotonin syndrome)
CYP2 D6 polymorphism- autosomal recessive trait (slow or ultra-rapid metabolisers)
Tricyclic antidepressants (Lofepramine)
Venlafaxine MAOIs
Antidepressant drugs:
- Induction of mania/mixed states - Cycle acceleration (rapid cycling) - Uncertainty about duration of Rx
Choice of medicationChoice of medication
Severity of illnessClinical presentationSuicidal riskPrevious response to treatmentThe likely tolerability of potential side effectsThe likely benefit of potential side effects such as sedationThe likely drawbacks of potential side effects such as sedation (i.e. working with machinery, driving etc)Pregnancy or breastfeedingConcomitant treatment of physical illness or other psychiatric disorders with the potential for pharmacokinetic/pharmacodynamic interactions.The presence of relevant physical (for example cardiovascular) disease
Therapeutic alliance Adequate information about the nature of their illness and the
need for treatment. A positive message about the treatability Explain that antidepressants are not addictive, do not alter
one’s personality nor affect their intelligence. It may take about 2 -4 weeks before s/he their symptoms
start showing significant improvement They may experience some side effects Antidepressant could be changed if they are unable to
tolerate the original drug prescribed. Regular reviews of the patient’s mood state and suicidal risk
offers further reassurance and support, helps ensure compliance and allows prompt intervention in the case of any serious worsening of the condition.
1960s-70s First generation – “classical”First generation – “classical”
Phenothiazines - chlorpromazine Butyrophenones - haloperidol Thioxanthines - flupenthixol
From 1980s Second generation – “atypicals”Second generation – “atypicals”
Clozapine, olanzapine, quetiapine, Sulpiride, amisulpride
Risperidone, paliperidone Aripiprazole
ExtrapyramidalExtrapyramidalParkinsonism
DystoniaAkathisia
Tardive dyskinesia
Hyperprolactinaemia Hyperprolactinaemia AmenorrhoeaLow fertility
Sexual dysfunction
Cardiovascular – QT intervalHaematological
Weight gainLower seizure threshold
Drug interactions
EPS Prevalence Rx
parkinsonism 30% anticholinergic drugsamantadine
dystonia 21%(young males)
anticholinergic drugs
akathisia 25% - 75% propranolol
tardive dyskinesia 10-20%(>1year Rx)
*
neurolepticmalignant syndrome
Males>females bromocriptinedantrolenediazepam
Effective – when 60% D2 receptor occupancy
EPS - when 80% D2 receptor occupancy (shown on PET scanning)
SchizophreniaSchizophrenia Bipolar disorderBipolar disorder
ObesityObesity 45-55%45-55% 26%26%
SmokingSmoking 50-80%50-80% 55%55%
Diabetes Diabetes mellitusmellitus
10-14%10-14% 10%10%
Hypertension Hypertension >18%>18% 15%15%
Reasons for intolerance (total 15%) weight gain/metabolic – 4%
EPS – 4% Sedation – 2% Other – 5%
Efficacy on +ve and -ve symptoms no difference between 1st and 2nd
generation
Electrolyte imbalance ( ↓K, ↓Mg)
Underlying cardiac abnormalities
Hypothyroidism
Familial QT prolongation Σ
Drugs known to prolong QT
Higher risk of QTc prolongation and Torsades de Pointes – iv administration or high doses
Recent recommendation an ECG to be performed prior to Rx
Great variation in pharmacological profile!
In general they have decreased likelihood of extrapyramidal effects or
hyperprolactinaemia
BUT
Weight gainDiabetes
Metabolic syndrome
First generationFirst generation Second generationSecond generation
Weight gain
Hyperglycaemia, diabetes
Insulin resistance
Cardiovascular dis
Dyslipidaemia
Less EPS
Less QT prolongation
Less hyperprolactinaemia
Neurological side effects
EPS
Tardive dyskinesia
Hyperprolactinaemia
5.1
9.8
7.9
18.0
23.0
29.0
3.7 4.05.0
9.0
6.0
3.00
5
10
15
20
25
30
Aripiprazole** Ziprasidone PALI*** Risperidone Quetiapine Olanzapine
Per
cen
t o
f P
atie
nts
(%
) Drug Placebo
* Based on USPIs** Error bars reflect reporting of w eight gain in PI by baseline BMI*** Based on SCH-303, 304, 305 pooled dataset (all doses)
Antipsychotic drugs Schizophrenia, other psychoses and any psychotic
symptoms- sometimes useful as sedatives
- Antidepressants- Depression- Anxiety- Obsessive compulsive disorder
Drug treatment needs to be tailored to the individual
The aim is to achieve full symptom controlReturn to pre morbid functioning
Minimize side effects, ensure safetyMonitor progress over time as mental
illnesses are long term relapsing conditionsAlways check suicide risk