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