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