Drugs Used in Psychiatry
Dr Noel Kennedy Clinical Lecturer and Consultant
Psychiatrist
Schizophrenia
• Positive symptoms
- delusions
- hallucinations
• Negative symptoms
- apathy
- avolition
Schizophrenia – Diagnosis (Schneider, 1959)
• Hallucinations - third person - running commentary - thought echo
• Thought interference or Somatic passivity
• Delusional perception (also bizarre delusions DSM-IV, one month duration0
Schizophrenia - Epidemiology
• 1% prevalence, higher cities, ethnic minorities
• M>F, late teens to early 20s
• Two peaks in onset - early onset, male, developmental delay, drugs - late mid-life, female, preserved personality
• Interst in substance abuse, prenatal viral exposure
• Poor outcome - >80% relapse, majortiy impaired
Schizophrenia Aetiology
• Genetic
- First degree relative 10%
- Twin studies MZ:DZ 48:4, Adoption studies
• Neurochemical
- D2 blockade (amphetamines, animal models, receptor occupancy)
- Serotonin blockade (?5HT2 block, LSD,.5HT impact on dopamine )
- Glutamate (NMDA antagonists e.g. ketamine)
Antipsychotics- Classification
H igh po ten cy(h igh a ffin i ity D 2)
L o w po ten cy( lo w a ff in i ty D 2)
T yp ica l (D 2)(m o re E P S E )
A typ ica l (5 H T 2 /D 2)( le ss E P S E )
A n tip sych o tics
Typical antipsychotics D2 Antagonism
Mesolimbic
(Antipsychotic)
HPA
(↑ PRL)
Basal Ganglia
(EPSE, Parkinsonism)
Typical Antipsychotics
• High potency “Clean” (Likely EPSE)
- Butyrophenones (e.g. haloperidol)
- Piperazine (e.g. trifluoperazine)
• Low potency “Dirty” (anticholinergic, antiadrenergic)
- Aliphatic (e.g. chlorpromazine)
- Thioxanthene (Zuclopenthixol)
Extrapyramidal Side Effects
• Acute Dystonia (Young men, early, first episode)
• Parkinsonism (cog-wheeling, rigidity, bradykinesia)
• Akathesia (uncontrollable restlessness, suicide risk)
• Tardive Dyskinesia (long-term tx, female, elderly)
• Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome (NMS)• Early in tx (<4 weeks) M>F, 20% mortality,mid-life
• Clinical - muscle rigidity - pyrexia - delirium - pyrexia - ↑↑CPK, ↑K ↓Neutorophils, Myoglobinurea
• Treatment - respiratory support - bromocriptine/dantrolene
Antipsychotics Other Side Effects• Anticholinergic (low potency) - blurred vision, constipation, confusion, wt gain
• Antiadrenergic (low potency)
- postural hypotension, sexual
• ↓ Seizure threshold• Weight gain (low potency, clozapine, olanzapine)• Neutropenia/Agranulocytosis (clozapine)• Diabetes/Impaired GTT (clozapine, olanzapine)• Cholestatic jaundice (chlorpromazine)• ECG change, QT prolongation (low effect)
Atypical Antipsychotics
• Definitions
- Less EPSE
- Mesolimbic specific or 5HT2/D2 antagonism
• Clinical Potency
- As effective as typicals in positive symptoms
- Some more effective (clozapine>olanzapine/sulpiride>rest Davis et
al.)
- May have more effect on negative symptoms
Atypical Antipsychotics • Sulpiride/Amisulpiride - D2 blockade mesolimbic specific, ↑PRL antidepressant
• Risperidone - 5HT2/D2 blockade, EPSE high doses, little sedation, wt gain
• Olanzapine - 5HT2/D2 blockade, significant weight gain (9%), sedation • Quetiapine - D2/5HT2/ blockade, sedative, few other s/e, ?potency • Clozapine - treatment resistant scz, multiple receptors, agranulocytosis
Clozapine
• Most effective treatment for treatment resistant schizophrenia (30% 6 weeks, 70% 1 year kane et al, 1988)
• Multiple receptor occupancy
(D1, D2, D4, D5, 5HT2, 5HT3, adrenergic, muscarinic)
• Many side effects including agranulocytosis (2-3%)
• May lead to reduction in suicide
Clozapine Important Side Effects • Neutropenia - Weekly blood monitoring (18 weeks), 2-4 weeks afterwards
• Seizures - Mainly myoclonic, dose related, valproate
• Myocarditis/Cardiomyopathy - 1 in 10,000-20,000 • Pulmonary embolism - 1 in 5,000, effect on antiphospholipid antibodies
• Diabetes and weight gain - 1/3rd within 5 years of treatment
Clozapine Other Side Effects • Sedation (early)
• Hypersalivation (hyoscine) • Hypertension/hypotension • Tachycardia (early)
• Constipation
• Fever
Antipsychotics and Diabetes
• Especially clozapine and olanzapine (30-40% diabetes long-term)
• Usually early in treatment
• Needs regular monitoring
(Baseline HBA1C, OGTT, then 3-6 monthly)
Depression Treatment: Symptoms • At least two of (>2 weeks): - persistent low mood (DMV) - anhedonia - poor energy • At least two of: - sleep disturbance - appetite disturbance/weight loss - impaired libido - guilt & cognitions - poor concentration - futility feelings/suicidal ideation - social withdrawal
Depression - Epidemiology
• 6-9% prevalence, higher women (F:M 2:1)
• Late 20s throughout life
• Higher rates cities, low social class
• Poor outcome – high levels of disability - 10% chronicity - 10% unnatural death - 70% long-term recurence - 50% of time symptomatic over 10 years
Depression and subsyndromal symptoms over 10-year follow-up (Kennedy et al, 2004)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Ye
ar 1
Ye
ar 2
Ye
ar 3
Ye
ar 4
Ye
ar 5
Ye
ar 6
Ye
ar 7
Ye
ar 8
Ye
ar 9
definite criteria
residual
minor symptoms
asymptomatic
Theories of Depression
• Monoamine Theory
- Deficits of monamines 5HT/Nad
- Most antidepressants increase monoamines
• Neuroendocrine (HPA axis)
- Hypercortisolaemia/loss of circadian rthymn
- Failure of DST (60%)
- Failure to supress CRH
Antidepressants Classes• Monoamine oxidase inhibitors (MAOI)
- ↑stores Nad/5HT by inhibiting MAO-A
• Tricyclic antidepressants (TCA) – inhibits 5HT/Nad neuronal reuptake
• Selective serotonin reuptake inhibitor (SSRI) – inhibits 5HT neuronal reuptake
• Others
- venlafaxine - Nad/5HT reuptake/receptor inhibition
- mirtazepine - alpha 2, 5HT2 receptor inhibition
- reboxetine – Nad reuptake inhibitor
Management of Depression: General Principles • Antidepressants only effective (70%)
• Partial response a problem (40%)
• Length of treatment important (4-8 weeks)
• Not all antidepressants are equal (meta-analysis)
• Consider symptoms
• Consider side efffects
• Length of continuation/maintenance treatment
Consider Symptoms and Side Effects
Mood
Sleep
Loss of pleasure
NE 5HT
Attention
Drive
Appetite
Obsessions
Anxiety
Cognitions
Selective Serotonin Reuptake Inhibitors (SSRI)
• First line treatment
• Effective in anxiety
• Safe, flat dose response
- Escitalopram - ? More efffective than citalopram - Fluoxetine – long t1/2, potent inhibition CYP - Paroxetine – short t1/2, discontinuation - Sertraline – mild CYP inhibition
Selective Serotonin Reuptake Inhibitors (SSRI)
• Common adverse effects - nausea, vomiting, abdo pain, diarrhoea - sweating - headache - agitation, insomnia, tremor
- hyponatraemia (SIADH) elderly, female,
- discontinuation syndrome (paroxetine) - sexual dysfunction
Tricyclic Antidepressants (TCA)
• Probably more effective than SSRI• S/E Anti chol, anti adren, anti hist action• Cardiotoxic OD, QT prolongation• Weight gain long-term• Doses prescribed too low
- Amitriptyline – sedation, anti chol, ↓BP postural - Clomipramine – similar s/e, 5HT anxiety/OCD - Loferpramine – less cardiotoxic, sedative - Nortriptyline – less s/e, elderly
Monoamine Oxidase Inhibitors (MAOI)
• Mode of Action
- Block MAO A (Nad/5HT) and B (Dop/TYP)
- Avoid tyramine containing substances- ↑↑BP
• Clinical Potency
- Best for atypical or resistant depression
- Withdrawal 2 weeks, withdrawal effects, 5HT syndroms
- Mocclobemide – Reversible MAO A inh
- Phenelzine/tranylcypromine – irreversible inh, non selective
Monoamine Oxidase Inhibitors (MAOI)
• NB Lots of S/E MCQ answer yes
- anti cholinergic/anti adrenergic/anti histamine - paraesthesia - headache - hepatotoxicity - leucopenia - hypertensive crises (9%) - sexual dysfunction
Other Antidepressants
• Venlafaxine - 5HT/Nad reuptake inhibitor like clomipramine - meta-analysis higher proportion recovery - linear dose response - s/e discontinuation, short t1/2, BP, SSRI like • Mirtazepine - 2 antagonist, wt gain, sedation
• Reboxetine - selective Nad antagonist• Duloxetine - 5ht/Nad reuptake inhibitor
Electroconvulsive Therapy
• Most effective in TRD (80-85% response) • Well tolerated (6-12 treatments)• Best severe, agitated, elderly, depression
• ↑Nad/5HT transmission, Da, PRL +oxyticin release, ↑plasma cortisol, ↑BBB permiability
• Adverse effects
headache, muscle stiffness, memory, GA
Refractory Depression: Definitions
• Failure to respond fully to >1 or several antidepressants (10-30%)
• Chronic duration <2 years (10%) - least likely to be effectively treated
• Partial response also a problem (>40%)
Management of TRD• Outrule medical cause/medications
(e.g. diabetes, hypothyroidism, Cushing’s syndrome, dementia)
• Investigate precipitants of depression (e.g. bereavement, marital or family
dysharmony, social factors)
• Consider comorbidity or misdiagnosis (e.g. anxiety disorders, substance abuse,
dementia)
Management of TRD
• Psychoeducational
- self-help books
• Pharmacological
- optimise antidepressant treatment
- switch class of antidepressant
- augment antidepressant
• Psychological
- CBT/interpersonal psychotherapy prevents early relapse
-
Management of TRD: Augmentation
• First: low dose lithium
50% response within 1 week
• Second: low dose atypical antipsychotics • Third: Triiodothronine (T3), lamotrigine, tryptophan
• Fourth: Combine antidepressants
↑
Anxiety Disorders Types
- Generalized Anxiety Disorder
- Social phobia
- Agoraphobia
- Obsessive Compulsive Disorder
Treatment
- Exposure therapy
- SSRIs and Clomipramine, Benzos (<2 weeks)
Bipolar Affective Disorder - Epidemiology
• 0.8% prevalence, women later onset (F:M 1.2:1)
• Onset early 20s, 50% mania,
• Higher rates cities, ?higher social class
• Strongly genetic (20% first degree relative)
• Very high proportion recur (>90%)
• Women more depression BPII>BPI
Management of BAD: Acute
• Treatment of mania
- Antipsychotics or benzodiazepines
- (semi)sodium valproate/lithium
• Treatment of bipolar depression
- Lithium treatment of choice
- Lamotrigine
- Antidepressants – risk of inducing mania/rapid cycling
Management of BAD: Maintenance
• Moderate dose lithium (0.8-1.2 meq/l)
(60-70%), prevents mania and depression
• Valproate>Cambamazepine• Better for mania than depression • Lamotrigine• Better for depression than mania
• Atypical antipsychotics – recent data
Lithium • Acute and maintenance (depression>mania)
• Mode of action
- salt, not metabolised, 2/3 excreted by 24 hrs, Avoid NSAID + ACE Inh
- G proteins, Na/K ATP ase, cAMP
• Side effects
- Immediate: dry or metallic taste, diarrhoea, tremor
- Nephrogenic diabetes insipitus polydipsia/polyurea (ADH resistance)
- Later: Nephropathy (5%), Hypothyroidism (3% pa), weight gain/oed
- Toxicity: (.2.0 meq/l) coarse tremor, confusion, ataxia, coma
Other Mood Stabilizers• All are anticonvulsants and act on Na channels and GABA
• Valproate
- Acute mania, maintenance, rapid cycling
- S/E – sedation, weight gain, hair loss, hepatic failure, leucopenia, terato
thrombocytopaenia, highly plasma protein bound, displacement
• Cambamezipine
- Acutr mania, rapid cycling, agression S/E leucopenia (10%) agran, sed
apl anaemia, enzyme inducer OCP, rash Stevens-Johnson syndrome
- Lamotrigine
- Bipolar dsepression S/E rash, headache, nausea, ataxia
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