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  • While treatment for depression has evolved over the decades and side-effect profiles and interaction profiles have improved dramatically compared with those known to be associated with monoamine oxidase inhibitors and tricyclic antidepressants (TCAs), much work remains to be done In response to treatment of first choice, a significant proportion of patients fail to reach acceptable levels of function and well-being In short-term, placebo-controlled clinical trials, about a third of patients achieve partial or no response 1 and only about a third achieve remission 2 References Fawcett J. Barkin RL. Efficacy issues with antidepressants. Journal of Clinical Psychiatry 1997; 58 (Suppl 6): 32 – 39. O'Reardon JP, Amsterdam JD. Treatment-resistant depression: progress and limitations. Psychiatric Annals 1998; 28 : 633 – 640.
  • The presence of residual symptoms of depression was associated with a relapse rate of 76% compared with a relapse rate of 25% among patients who did not have residual symptoms Reference Paykel ES. Ramana R. Cooper Z. Hayhurst H. Kerr J. Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychological Medicine 1995; 25 (6): 1171 – 1180.
  • The objectives for the treatment of depressed patients are to: Achieve remission (acute treatment) Prevent relapse (continuation treatment) Prevent recurrence (maintenance treatment) 1 A response is defined as a 50% improvement in symptoms as measured by the HAM-D score 2 Remission is a virtually symptom-free state – the HAM-D score is ≤ 7 3 Relapse is a worsening of symptoms after remission 1 Recurrence is the development of a new episode after initial recovery 1 The risk of relapse is significantly higher in patients that respond only partially to therapy compared with those who achieve remission (76% versus 25%) 4 Reference 1. Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry 1991; 52 (5, Suppl):28–34. 2. Fawcett J, Barkin RL. Efficacy issues with antidepressants. J Clin Psych 1997; 58 (suppl 6):32–38. 3. Ballenger JC. Clinical guidelines for establishing remission in patients with depression and anxiety. J Clin Psych 1999; 60 (suppl 22):29–34. 4. Paykel ES. Ramana R. Cooper Z. Hayhurst H. Kerr J. Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychological Medicine 1995; 25 (6): 1171 – 1180.
  • KEY POINTS: Both serotonin (5-HT) and noadrenaline (NA) are neurotransmitters that have ascending tracts to the cerebral cortex and limbic area, as well as descending tracts to the spinal cord 1 The cell bodies for these tracts originate in major nuclei of the midbrain. For the central nervous system, the 5-HT cell bodies are located in the raphe nuclei and the largest cluster of NA cells are located in the locus coeruleus 1 Each of these midbrain nuclei has ascending tracts, which project to brain regions thought to be involved in depressive symptoms, as well as ascending and descending tracts involved in pain suppression The monoamine theory of depression suggests that a relative deficiency in synaptic levels of serotonin and noradrenaline in key central nervous system pathways underlies depressive illness (CNS = brain + spinal cord) 2,3,4 5-HT- and NA -secreting neurons project upward from their respective nuclei in the brainstem, directly stimulating many areas of the brain Brain areas stimulated include the prefrontal cortex, which is involved in executive functions, and the limbic system which include anatomical structures involved in behaviour, motivation, and emotion, such as the hippocampus, anterior cingulate cortex, hypothalamus, and amygdala 1 REFERENCES: Mega MS, Cummings JL, Salloway S, Malloy P. The limbic system: An anatomic, phylogenetic, and clinical perspective. J Neuropsychiatry Clin Neurosci 1997;9:315-330. Hales RE, Yudofsky SC. Mood disorders. In: Textbook of Clinical Psychiatry . 4th ed. Arlington: American Psychiatric Publishing; 2003:479-486. Coppen A. The biochemistry of affective disorders. Br J Psychaitry 1967;113:1237-64 Schildkraut JJ. The catacholamine hypothesis of affective disorders. A review of supporting evidence. Int J Psychiatry 1967;4:203-17
  • Core slide For the past 30 years, the leading theory to explain the biological basis of depression has been the monoamine hypothesis. This theory proposes that depression is due to deficiency of one or more monoamine neurotransmitters in the brain. Evidence to date mainly implicates serotonin and noradrenaline. The left diagram illustrates a serotonergic and noradrenergic neurone , in the normal state , releasing serotonin and noradrenaline . All of the cell’s regulatory elements are also functioning properly . In depression, as shown in the diagram on the right, serotonin and noradrenaline are depleted .
  • Core slide For the past 30 years, the leading theory to explain the biological basis of depression has been the monoamine hypothesis. This theory proposes that depression is due to deficiency of one or more monoamine neurotransmitters in the brain. Evidence to date mainly implicates serotonin and noradrenaline. The left diagram illustrates a serotonergic and noradrenergic neurone , in the normal state , releasing serotonin and noradrenaline . All of the cell’s regulatory elements are also functioning properly . In depression, as shown in the diagram on the right, serotonin and noradrenaline are depleted .

Palazidou 03 Palazidou 03 Presentation Transcript

  • 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-D 17 Rating Scale Depressed patients with unresolved symptoms are 3 times more likely to relapse 1
  • Kupfer DJ. J Clin Psychiatry 1991; 52 (5, Suppl): 28–34.
    • 1. Acute Treatment
    • First 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 Treatment
    • Aims at prevention of recurrence of a further episode of depression.
    • Indicated when higher risk of these recurrence.
    • “ maintenance dose”
  • Treatment aims Complete symptom resolution Return to premorbid functioning (psychosocial, occupational) The maintenance of normality The prevention of recurrence
  • Limbic System Prefrontal Cortex Locus Coeruleus (NA source) Raphe Nuclei (5-HT source) Amygdala Hippocampus Cooper JR, et al. The Biochemical Basis of Neuropharmacology . 8th ed. New York: Oxford University Press; 2003. Descending 5-HT pathways Descending NA 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 SSRIs Citalopram(Cipromil), Fluoxetine (Prozac), Fluvoxamine(Faverin), Paroxetine(Seroxat), Sertraline (Lustral) 5-HT re uptake inhibition MAOIs Phenelzine(Nardil), Isocarboxazid(Marplan) Tranylcypromine(Parnate) Inhibition of MAO-A and MAO-B isoenzymes Interaction with tyramine and sympathomimetic drugs; Irreversible and non-selective inhibition of MAO isoenzymes RIMAs Moclobemide(Manerix) Reversible Inhibition of MAO-A SNRIs Venlafaxine(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 effects ↑ Weight, sexual dysfunction, dry mouth, headache Safety in overdose Lethal (hypertensive crisis, stroke,MI) Sympathomimetics ¢ Tyramine foodstuffs ¢ Carbamazepine ¢ Hypertensive crisis β -blockers ↑ hypotension,bradycardia Oral hypoglycaemics ↑ hypoglycaemic effect SSRIs ¢ Nefazodone Serotonin Syndrome Bupropion ¢ Hypertensive crisis, seizures Clomipramine ¢
  • SIDE EFFECT PROFILE OF TRICYCLIC ANTIDEPRESSANTS Anticholinergic Dry mouth, Blurred vision Urinary hesitancy (urinary retention) Constipation Memory impairment Aggravation of narrow angle glaucoma Antihistaminic Sedation Weight gain Alpha1 adrenoceptor antagonism Orthostatic hypotension Cardiac effects Cardiovascular effects Sinus tachycardia Arrhythmias Conduction delay Sudden death Other side effects Sexual dysfunction Impaired cognitive and psychomotor skills Convulsions
  • SIDE EFFECT PROFILE OF SSRIs Nausea/vomiting* Abdominal pain Dry mouth Constipation/diarrhoea Headache* Asthenia Dizziness Insomnia/somnolence Sweating* Anorexia Weight loss Nervousness/agitation Tremor Convulsions Dystonic reactions Sexual 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)
      • agitation
      • myoclonus
      • hyperreflexia
      • diaphoresis
      • shivering
      • tremor
      • diarrhoea
      • incoordination
      • fever
    • Other 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 SYNDROME
    • Dizziness *
    • Electric shock sensations *
    • Anxiety/agitation ٭
    • Insomnia
    • Flu-like symptoms
    • Diarrhoea/abdominal spasms
    • Paraesthesia *
    • Mood swings
    • Nausea
    • Low 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 medication
    • Severity of illness
    • Clinical presentation
    • Suicidal risk
    • Previous response to treatment
    • The likely tolerability of potential side effects
    • The likely benefit of potential side effects such as sedation
    • The likely drawbacks of potential side effects such as sedation (i.e. working with machinery, driving etc)
    • Pregnancy or breastfeeding
    • Concomitant 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
    • T hey may experience some side effects
    • A ntidepressant 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”
    • Phenothiazines - chlorpromazine
    • Butyrophenones - haloperidol
    • Thioxanthines - flupenthixol
    • From 1980s
    • Second generation – “atypicals”
    • Clozapine, olanzapine, quetiapine,
    • Sulpiride, amisulpride
    • Risperidone, paliperidone
    • Aripiprazole
  •  
    • Extrapyramidal
    • Parkinsonism
    • Dystonia
    • Akathisia
    • Tardive dyskinesia
    • Hyperprolactinaemia
    • Amenorrhoea
    • Low fertility
    • Sexual dysfunction
    • Cardiovascular – QT interval
    • Haematological
    • Weight gain
    • Lower seizure threshold
    • Drug interactions
  • Effective – when 60% D2 receptor occupancy EPS - when 80% D2 receptor occupancy (shown on PET scanning ) EPS Prevalence Rx parkinsonism 30% anticholinergic drugs amantadine dystonia 21%(young males) anticholinergic drugs akathisia 25% - 75% propranolol tardive dyskinesia 10-20% (>1year Rx) * neuroleptic malignant syndrome Males>females bromocriptine dantrolene diazepam
  • Schizophrenia Bipolar disorder Obesity 45-55% 26% Smoking 50-80% 55% Diabetes mellitus 10-14% 10% Hypertension >18% 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 1 st and 2 nd 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 gain
    • Diabetes
    • Metabolic syndrome
  • First generation Second generation Weight gain Hyperglycaemia, diabetes Insulin resistance Cardiovascular dis Dyslipidaemia Less EPS Less QT prolongation Less hyperprolactinaemia Neurological side effects EPS Tardive dyskinesia Hyperprolactinaemia
  •  
    • 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 control
    • Return to pre morbid functioning
    • Minimize side effects, ensure safety
    • Monitor progress over time as mental illnesses are long term relapsing conditions
    • Always check suicide risk