Psychopharmacology

Question 1

Antidepressants

Answer 1

• Increase serotonin (5HT) and/or noradrenaline (NA)
• Different antidepressants vary in:
  
  • Effect on 5HT or NA
  • Effects on other receptors
  • Half-life, interactions and toxicity

Question 2

Selective Serotonin Reuptake Inhibitors (SSRIs)

Answer 2

• Fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram
• Usually 1st line
• Side effects:
  
  • Gastrointestinal
    • Common: Nausea, appetite loss, dry mouth, diarrhoea, constipation, dyspepsia.
    • Uncommon: vomiting, weight loss.
  • CNS
    
    • Common: insomnia, dizziness, anxiety, fatigue, tremor and somnolence.
    • Uncommon: EPS, seizures and mania.
  • Other
    
    • Common: sweating, delayed orgasm and anorgasmia.
    • Uncommon: hyponatraemia and alopaecia.
• Fluoxetine has longest half-life and least discontinuation
• Sertraline used in people with lots of comorbidities
• Paroxetine has gretest risk of discontinuation, used in OCD

Question 3

Noradrenaline Reuptake Inhibitors (NARIs)

Answer 3

• Reboxetine
• Action - NA
• Less effective

Question 4

Tricyclic antidepressants (TCAs)

Answer 4

• Block 5HT and NA (as well as lots of other receptors)
• Very effective
• Lots of side effects
• Overdose dangerous and can cause seizures, coma and arrthymias
• SRI - depression lifts
• NRI - depression lifts
• H1 inserted - weight gain, drowsiness
• α inserted - dizziness, low BP
• M1 inserted - constipation, dry mouth, blurred vision, drowsiness

Question 5

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

Answer 5

• Venlafaxine, Duloxetine
• Better tolerated than TCAs
• Possibly more effective than SSRIs for severe depression
• Used 2nd/3rd line
• Prominent side effect - sexual dysfuction

Question 6

Noradrenaline and specific antidepressants (NaSSAs)

Answer 6

• Mirtazepine
• Blocks α 2 receptors - Increases 5-HT release
• Blocks 5-HT2 and 3 receptors - anxiolytic effect
• Blocks H1 receptors - Sedation, Weight gain
• Relatively safe in overdose
• Used 2nd/3rd line

Question 7

Monoamine Oxidase Inhibitors (MAOIs)

Answer 7

• Inhibit monoamine oxidase
  
  • A - NA, 5HT, DA, Tyramine
  • B - DA, Tyramine, others
• Phenelzine, isocarboxazid, tranylcypromine (PIT) - inhibit MAOA and B irreversibly
• Moclobemide - inhibits MAOA reversibly
• Tyramine in the diet is a potential releaser of NA - NA broken down by MAOA in the brain and gut, if MAOA is inhibited then tyramine can lead to a hypertensive crisis

Question 8

Antipsychotics

Answer 8

• D2 + 5HT2a + HAM antagonism
• Dopamine receptor antagonism can effect 4 brain pathways:
  • Mesolimbic (positive symptoms and reward - blockage causes anhedonia etc)
  • Mesocortical (deficiency in dopamine leads to negative symptoms - worsen cognition)
  • Nigrostriatal (extrapyramidal effects - Parkinsonism and tardive dyskinesia)
  • Tuberoinfundibular (prolactin - galactorrhoea, infetility)

Question 9

Types of antipsychotics

Answer 9

• Typical/1st generation - mainly D2
  
  • Chlorpromazine
  • Flupentixol (Depixol)
  • Haloperidol
  • Sulpride
  • Zuclopenthixol (Clopixol)
• Atypicals/2nd generation (QOAARC) - mixed D2 and 5HT2A effect so less EPSE and hyperprolactinaemia, more metabolic syndrome
  
  • Quetiaprine
  • Olanzapine
  • Amisulpiride
  • Aripiprazole
  • Risperidone
  • Clozapine (can cause agranulocytosis - fatal)
• Clozapine levels go up when patient stops smoking and side effects include sialorrhoea, seizures, myocarditis, agranulocytosis, sedation, constipation and sudden hyperglycaemia
• Monitoring includes weight, BP, ECG, glucose/HbA1c, lipids and remind patient to wear sunscreen

Question 10

Lithium

Answer 10

• Multiple mechanisms
• Narrow therapeutic index - monitor levels every 3 months
• Renal and thyroid dysfunction
  
  • Renal function + TFTs 6 monthly, calcium annually
• Sudden discontinuation has 50% risk of mania
• Teratogenic - Ebstein’s anomaly

Question 11

Valproate (mood stabiliser)

Answer 11

• Multiple actions (including GABA)
• Not for women of child bearing potential - Teratogenicity (neural tube defects)
• Side effects include nausea, tiredness, weight gain, hair loss with curly regrowth

Question 12

Carbamazepine (mood stabiliser)

Answer 12

• Na channel blocker
• Side effects include nausea, headaches, dizziness, dry mouth, low WCC, raised LFT

Question 13

Lamotrigrine (mood stabiliser)

Answer 13

• Slow dose titration
• Risk of SJS

Question 14

Hypnotics/Anxiolytics

Answer 14

• Benzodiazepines
  
  • GABA
  • Diazepam, lorazepam, temazepam (-zepam)
  • Tolerance after >4 weeks
• Z-drugs
  
  • GABA
  • Zopiclone, zolpidem
• Pregabalin - Ca channels
• Buspirone - 5HT1A agonist
• Propranolol, atenolol – beta blocker
• Antidepressants
• Sedative antipsychotics

Question 15

Aversive drugs

Answer 15

• Disulfiram (Antabuse) - aldehyde dehydrogenase inhibitor (alcohol > acetaldehyde (↑) > acetate)
• Acamprosate - alcohol cravings
• Opiate antagonists - Nalmefene – alcohol (reduced enjoyment), Naltrexone – opiate abuse

Question 16

Cognitive enhancers

Answer 16

• Acetylcholinesterase (AChE) Inhibitors
  
  • Increase ACh
  • Donepezil, Galantamine, Rivastigmine
• NMDA antagonists (neuroprotective)
  
  • Memantine

Question 17

Stimulants

Answer 17

• ADHD, Narcolepsy
• Action – increase DA and/or NA
• Methylphenidate and Dexamfetamine
  
  • DA and NA RI
• Atomoxetine – NA RI
• Modafinil – DA and NA releaser

Question 18

Electroconvulsive Therapy (ECT)

Answer 18

• Seizure – improves mood and psychotic symptoms
• One of the safest treatments
• Least side effects
• Fastest acting – life saving
• Indications
  
  • Severe depression
  • Suicidal ideation, psychomotor retardation
  • Catatonia
  • Treatment resistant psychosis
• No absolute contraindications
• Usually twice a week, up to 12 sessions
• Patient needs to give consent or 2nd opinion from MWC
• Risks are mainly from anaesthetic, dentition, headache, muscle pains, vomiting and long-term memory can be affected

Question 19

Psychosurgery

Answer 19

• Lobotomy – not done anymore
• Anterior cingulotomy (targets anterior cingulate cortex – part of limbic system)
• Treatment resistant mood disorder
• Treatment resistant OCD
• Other treatments
  
  • Transcranial Magnetic Stimulations (TMS)
  • Vagal Nerve Stimulation (VNS)

Question 20

Adverse affects of antipsychotics

Answer 20

• Movement disorders
  
  • Acute dystonia ( <10%) - Involuntary contraction of skeletal muscle. e.g. torticollis or oculogyric crisis. More commonly younger males, neuroleptic naïve.
  • Pseudo-parkinsonism (<40%) - Tremor, rigidity and hypokinesia. Dopamine blockade of nigro-striatal pathways implicated aetiologically.
  • Akathisia(<30%) - Characterised by motor restlsssness , a subjective feeling of tension and an inability to tolerate inactivity which gives rise to restless movement.
  • Tardive dyskinesia(<30%) - Late onset hyperkinetic, involuntary movements. Involves face, lips, tongue, jaw and neck, but which involve the trunck, arms and hands. Most common syndrome is the BLM syndrome (Bucco-linguo-masticatory Triad). Most importantly may be irreversible in 30% cases. Aetiology appears to be the increase in sensitivity of Dopamine receptors through up regulation from chronic blockade.
• Autonomic effects
  
  • Anti-adrenergic - Postural Hypotension,
  • ECG changes (QTC prolongation) with subsequent cardiac dysrythmias such as Torsade des pointes.
  • Sexual dysfunction – ejaculatory failure.
  • Anti-cholinergic Effects- dry mouth, blurring of vision, constipation, difficulty with micturition and urinary retention.
• Neuroleptic Malignant Syndrome (NMS). – is a potentially fatal condition that produces muscle rigidity, extreme EPS, severely elevated body temperature, hypertension, and tachycardia. If untreated can cause respiratory failure and cardiovascular collapse. Rare.
• Convulsant Activity – antipsychotics especially of the phenothiazine class (eg. Chlorpromazine) can lower seizure threshold. Individuals with established Epilepsy can show an increase in fit frequency.
• Pigmentation – possibly due to catalytic effect of ultraviolet light acting upon melatonin in presence of phenothiazines. Melanin therefore deposited in the skin.
• Metabolic Effects
  
  • Weight gain – Class effect with Clozapine and Olanzapine showing greatest propensity to weight gain.
  • Linked to Diabetes.
  • Multiple mechanisms include Serotonergic (5HT2C) subtype antagonism and anti-histaminic binding properties and interfrence with the Leptin system.
  • Hyperprolactinaemia through Tuberoinfundibular Dopamine pathway blockade in the pituaitary.
  • Effects are reduced libido, sexual dysfunction through impotence in males, menstrual irregularites and lactation in non-pregnant females.
• Hypersensitivity Reactions
  
  • Cholestatic Jaundice – frequently due to phenothiazine class but all antipsychotics can cause transaminase changes in liver.
  • Skin Reactions – Photosensitivity rashes and sunburns can occur in addition to urticarial or eczematous rashes.

Question 21

Adverse effects of Lithium

Answer 21

• Nausea
• Vomiting
• Diarrhoea
• Metallic taste in the mouth
• Cognitive “Dulling”
• Tremor
• Muscle weakness
• Weight Gain
• Hypothyroidism
• Hyperparathyoidism
• Renal Tubular Necrosis - Renal Failure
• Nephrogenic Diabetes Insipidus
• Toxicity (tremor, nausea, vomiting and dizziness to ataxia, dysarthria, drowsiness, coma, fits and death)

Question 22

Clinical features of serotonin syndrome

Answer 22

• Neurological : Myoclonus. nystagmus, headache, tremor, rigidity and seizures
• Mental state : irritability, confusion, agitation, hypomania, coma.
• Other : Hyperpyrexia, sweating, diarrhoea, cardiac arrhythmias, death.

NB: some of these symptoms resemble Neuroleptic Malignant Syndrome (NMS)