The following lecture has been approved for University Undergraduate Students

1. The following lecture has been approved for University Undergraduate Students This lecture may contain information, ideas, concepts and discursive anecdotes that may be thought provoking and challenging It is not intended for the content or delivery to cause offence Any issues raised in the lecture may require the viewer to engage in further thought, insight, reflection or critical evaluation

2. Psychopharmacology therapeutics The role of Serotonin Dr. Craig Jackson Senior Lecturer in Health Psychology Faculty of Health BCU craig.jackson@bcu.ac.uk

3. Depressive Illness Usually treatable Common Marked disability Reduced survival Increased costs Depression may be Coincidental association Complication of physical illness Cause of / exacerbate somatic symptoms

4. Depressive Illness 2% of population suffer frompure depression (evenly distributed between mild, moderate,and severe) Further 8% suffer from a mixture of anxietyand depression Patients with symptoms not severe enoughto qualify for diagnosis of either anxiety or depression..... Impaired working and social lives and many unexplainedphysical symptoms Greater use of medical services “Walking Well”

5. Classification Spectrum of mood disturbance Mild thru to Severe Transience thru to Persistence Continuous distribution in population Clinically significant when: (1) interferes with normal activities (2) persists for min. 2 weeks Diagnosis of depression / depressive disorder “Persistent & pervasive low mood” “Loss of interest or pleasure in activities”

6. Classification Most depressions have triggering life events - Reactive depression Especially ina first episode Many patients present initially with physicalsymptoms (somatisation) Some may show multiple symptoms ofdepression in the apparent absence of low mood - “Masked Depression” Some depression has no triggering cause - “Endogenous Depression” More persistent and resistant to treatment

7. Clinical Features & Diagnoses Adjustment Disorders mild short-lived reactive episodes Major Depressive Disorder (MDD) 5 symptoms displayed in 14 days Dysthmia depressed mood for 2+ years not severe chronic depression unhealthy lifestyle associations Bipolar Disorder / manic depression major depression & mania

8. Classification of Depression (ICD-10) • PrimaryUnipolar • Mixed anxiety and depressive disorder (prominent anxiety) • Depressive episode (single episode) • Recurrent depressive disorder (recurrent episodes) • Dysthymia - Persistent and mild ("depressive personality") • Bipolar • Bipolar affective disorder - manic episodes ("manic depression") • Cyclothymia - Persistent instability of mood • Other primary • Seasonal affective disorder • Brief recurrent depression • Depressive episode may be • Moderate or severe • With/Without somatic syndrome • With/Without psychotic symptoms

9. DSM IV criteria: Major depression 5 or more….. • decreased interest / pleasure * • depressed mood * • reduced energy • weight gain / loss • insomnia / hypersomnia • feeling worthless • guilt • recurrent morbid thought • psychomotor changes • fatigue • poor concentration • pessimism / bleak views • self harm ideas / actions • suicide ideation

10. DSM IV criteria: Major depression 4 or more... Anhedonia Loss of emotional reactivity Early waking (>2 hours early) Psychomotor retardation or agitation Marked loss of appetite Weight loss >5% of body mass in one month Loss of libido

11. Classification • Many patients do not fit neatly into categories of either anxietyor depression • Mixed anxiety and depressionis now recognised • Presence of physical symptoms indicatesa somatic syndrome • Value of somatic features in predicting response to treatmentis not clear • Presence of psychotic features has major implicationsfor treatment • Brief episodes of more severe depression arealso recognised • (brief recurrent depression) • More prolongedrecurrence is now termed recurrent depressive disorder

12. Epidemiology 2nd biggest cause of disability worldwide by 2020 (WHO) (IHD still the biggest) Associated with increased physical illness • 5% during lifetime have MDD • 1 in 20 consultations • 100 patients per GP • MDD & Dysthmia > in females • 20% develop chronic depression • 30% of in-patients have depressive symptoms

13. Epidemiology Depression more common in those with: Life threatened / limited / chronic physical illness Unpleasant / demanding treatment Low social support Adverse social circumstances Personal / family history of depression / psychological vulnerability Substance misuse Anti-hypertensive / Corticosteroid / Chemotherapy use

14. Drug Treatment Tricyclics since the 1950s effective and cheap dose-related anticholinergic side effects limit compliance variable degrees of sedation postural hypotension may fatal in overdose (except Lofepramine) Monoamine Oxidise Inhibitors (MAOI’s) rare fatalities tyramine-free diet Selective Serotonin Re-uptake Inhibitors (SSRI’s) fluoxetine lack sedation no anticholinergic effects improved compliance less immediate benefit for disturbed sleep safe in overdose single or narrow range of doses works

15. Psychiatric Diagnoses in Juvenile Offenders 93% Conduct Disorder 82% Substance Abuse Disorder 18% ADHD 26% Learning Disabilities 32% Anxiety Disorders 22% Mood Disorders 15% Associative Disorders Stanford University, Division of Child Psychiatry

16. Biology and Treatment of Aggression History and Relationship with Suicidal Behaviour The Role of Serotonin The Role of Other Neurotransmitters & Hormones Testosterone Cholesterol Opiates

17. Serotonin 5-Hydroxytriptamine 5-HT 5-HT is a neurotransmitter synthesised from amino acid Tryptophan Metabolised to 5-Hydroxyindole Acetic Acid (5-HIAA) Excreted in urine 3 - 15 mg/24hrs Elevated levels associated with tumors Normal Range of 101 - 283 ng/ml

18. The Association of Serotonin and Aggression Low 5-HT levels in suicide brains CSF 5-HIAA low after suicide Animal studies - inverse relationship between 5-HT and aggression e.g. Higley et al. 1992 - rhesus monkeys PD patients - inverse relationship between CSF 5-HIAA and history of aggression e.g. Brown et al. 1985 5-HT at heart of psychopharmacology for past 10 - 15 years

19. CSF 5-HIAA and Aggression in Patients Non-suicidal History n=15 Suicidal History n=9 5-HIAA ng/ml 00 20 40 60 0 4 8 12 16 20 24 Total Aggression Score Brown et al. 1979

20. Psychopathology of Disruptive Behaviour Disorders Stanford University, Division of Child Psychiatry Trauma Related Disorders Personality Disorders DISRUPTIVE BEHAVIOURDISORDERS Mood & Affective Disorders Substances

21. Violent Offender Studies Low 5-HIAA Impulsive Aggression History of Suicide Attempts Linoila et al. 1983

22. Suicide Studies Low 5-HT Transporters Low 5-HT2A Receptors Stanley et al. 1982

23. Pharmacotherapy for Impulsive Aggression Increase inhibitors Increase 5-HT Reduce Facilitators Reduce Catecholamines (adrenaline, noradrenaline, dopamine) SSRI’s can reduce CSF Vassopressin Levels (peptide hormone) SSRI’s can reduce overt aggression (Coccaro & Kavoussi 1997)

24. “Ecstacy” and MDMA Ecstacy stimulates serotoninProduces cells which turn on the areas of the prefrontal cortexGive feelings of euphoria, meaning and affectionsRegular users in danger of burning out the cellsCreating risk of temporary withdrawal symptoms and long-term risk of chronic depression.

25. Serotonin and MDMA use 40 minute cognitive task Frascella et al. 1999 Control Chronic MDMA user

26. Serotonin Hypothesis Pre-Synaptic 5-HT output reduced Post-Synaptic receptor sensitivity increased

27. Serotonin Pathway

28. Serotonin Neurotransmission

29. Fenfluramine Centrally active drug Benzeneethanamine, N-ethyl-alpha-methyl-3 (trifluoromethyl) Releases 5-HT & Blocks 5-HT uptake Provokes transport-mediated 5-HT release Leads to Prolactin response Treatment of obesity & several psychiatric disorders involving serotonergic systems

30. Phentermine Central Nervous System Stimulant Similar to Dextroamphetamine Benzeneethanamine, alpha, alpha-dimethyl

31. Fen-Phen Fenfluramine & Phentermine Combination therapy Wyaeth-Ayerst (Fen) $190 M in 1996 FDA powerless to stop it Some patients report anxiety, impulsion, aggression

32. Mood disorders are an illness - Treat them ! Drugs extremely effective Concentration, mood, and thought control restored Mood stabilizing drugs Role of Caffeine Tranquillizers & Antipsychotics acute episodic use only E.C.T effectiveness

33. Too much Serotonin? Increased 5-HT in CNS and receptor sites is therapeutic Benefits in... Depression Panic Disorder OCD Bulimia Toxic levels of 5-HT = fever, myoclonus, coma, seizure, cardiovascular collapse and death Fen-Phen related to cardiac damage - drug withdrawn

34. Too much Serotonin?

35. Selective Serotnin Re-uptake Inhibitors Greater selectivity at blocking 5-Ht re-uptake than norepinephrine re-uptake Lack Na channel blocking (tricyclic action) so safer in overdose Greater tolerability than tricyclics All SSRI’s are not the same Most SSRI’s bind to other receptors which are also responsible for their clinical actions Each SSRI has it’s own “portfolio” of effects

36. Not-So Selective? (1) norepinephrine reuptake, (2) dopamine reuptake, (3) serotonin-2C receptors, (4) muscarinic cholinergic receptors, (5) sigma receptors, (6) nitric oxide synthase, (7) cytochrome P450 2D6, (8) cytochrome P450 3A4, (9) cytochrome P450 1A2, and (10) cytochrome P450 2Cl9.

37. Review of the effects of 5 SSRI’s A meta-analysis of 20 short term comparative studies of 5 SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertralineNo difference in efficacy between compoundsSlower onset of action of fluoxetineFluoxetine may cause more agitation, weight loss and dermatological reactionsMore patients discontinued fluvoxamine Fewer patients stopped sertraline because of adverse effects than others Edwards & Anderson 1999

38. Review of the effects of 5 SSRI’s The most common adverse reactions to the SSRIs were:gastrointestinal (nausea) and neuropsychiatric - particularly headache and tremorCommittee on Safety of Medicines: more reports of reactions to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetinePrescription-event monitoring revealed higher incidence of adverse events related to fluvoxamine Fluoxetine not associated with a higher incidence of suicidal, aggressive and related events than the other SSRIs Edwards & Anderson 1999

39. Review of the effects of 5 SSRI’s Patients have survived large overdoses of each of the compoundsConcern expressed over 6 fatalities following overdoses of citalopramCitalopram should be avoided in patients likely to take overdoses. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, Fluoxetine may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptomsFluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions

40. Summary Role of Serotonin in behaviour can be clearly defined Behaviours more complex than just Serotonin SSRI’s produce good results in most patients SSRI’s advanced over older treatments SSRI’s more complicated than just Serotonin Re-uptake SSRI’s get a bad press from gen population and media Clinical use of SSRI’s requires careful balance of 5-HT in patient