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Psychopharmacology therapeutics The role of Serotonin
Dr. Craig Jackson Senior Lecturer in Health Psychology
Faculty of Health BCU
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
Depressive Illness
2% of population suffer from pure depression (evenly distributed between mild, moderate, and severe) Further 8% suffer from a mixture of anxiety and depression Patients with symptoms not severe enough to qualify for diagnosis of either anxiety or depression.....
Impaired working and social lives and many unexplained physical symptoms Greater use of medical services “Walking Well”
Classification
Spectrum of mood disturbance Mild thru to Severe Transience thru to 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” Persistence
Classification
Most depressions have triggering life events - Reactive depression Especially in a first episode Many patients present initially with physical symptoms (somatisation) Some may show multiple symptoms of depression in the apparent absence of low mood - “Masked Depression” Some depression has no triggering cause - “Endogenous Depression” More persistent and resistant to treatment
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
Classification of Depression (ICD-10)
Primary
Unipolar
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
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
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
Classification
• Many patients do not fit neatly into categories of either anxiety or depression • Mixed anxiety and depression is now recognised • Presence of physical symptoms indicates a somatic syndrome • Value of somatic features in predicting response to treatment is not clear • Presence of psychotic features has major implications for treatment • Brief episodes of more severe depression are also recognised (brief recurrent depression) • More prolonged recurrence is now termed recurrent depressive disorder
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
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
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
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
Biology and Treatment of Aggression
History and Relationship with Suicidal Behaviour The Role of Serotonin The Role of Other Neurotransmitters & Hormones Testosterone Cholesterol Opiates
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
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
CSF 5-HIAA and Aggression in Patients
Non-suicidal History Suicidal History n=15 n=9 Brown et al. 1979 0 4 8 12 16 20 Total Aggression Score 24
Psychopathology of Disruptive Behaviour Disorders
Trauma Related Disorders Personality Disorders DISRUPTIVE BEHAVIOUR DISORDERS Mood & Affective Disorders Substances
Stanford University, Division of Child Psychiatry
Violent Offender Studies
Low 5-HIAA Impulsive Aggression History of Suicide Attempts Linoila et al. 1983
Suicide Studies
Low 5-HT Transporters Low 5-HT 2A Receptors Stanley et al. 1982
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)
“Ecstacy” and MDMA
Ecstacy stimulates serotonin Produces cells which turn on the areas of the prefrontal cortex Give feelings of euphoria, meaning and affections Regular users in danger of burning out the cells Creating risk of temporary withdrawal symptoms and long-term risk of chronic depression.
Serotonin and MDMA use
40 minute cognitive task
Frascella et al. 1999 Control Chronic MDMA user
Serotonin Hypothesis
Pre-Synaptic 5-HT output reduced Post-Synaptic receptor sensitivity increased
Serotonin Pathway
Serotonin Neurotransmission
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
Phentermine
Central Nervous System Stimulant Similar to Dextroamphetamine Benzeneethanamine, alpha, alpha-dimethyl
Fen-Phen
Fenfluramine & Phentermine Combination therapy Wyaeth-Ayerst (Fen) $190 M in 1996 FDA powerless to stop it Some patients report anxiety, impulsion, aggression
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
Too much Serotonin?
Increased 5-HT in CNS and receptor sites is therapeutic Benefits in...
Depression OCD Panic Disorder Bulimia Toxic levels of 5-HT = fever, myoclonus, coma, seizure, cardiovascular collapse and death Fen-Phen related to cardiac damage - drug withdrawn
Too much Serotonin?
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
Not-So Selective?
(1) norepinephrine reuptake, (2) dopamine reuptake, (3) serotonin-2C receptors, (5) sigma receptors, (4) muscarinic cholinergic receptors, (6) nitric oxide synthase, (7) cytochrome P450 2D6, (8) cytochrome P450 3A4, (9) cytochrome P450 1A2, and (10) cytochrome P450 2Cl9.
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 sertraline No difference in efficacy between compounds Slower onset of action of fluoxetine Fluoxetine may cause more agitation, weight loss and dermatological reactions More patients discontinued fluvoxamine Fewer patients stopped sertraline because of adverse effects than others
Edwards & Anderson 1999
Review of the effects of 5 SSRI’s
The most common adverse reactions to the SSRIs were: gastrointestinal (nausea) and neuropsychiatric - particularly headache and tremor Committee on Safety of Medicines: more reports of reactions to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetine Prescription-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
Review of the effects of 5 SSRI’s
Patients have survived large overdoses of each of the compounds Concern expressed over 6 fatalities following overdoses of citalopram Citalopram 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 symptoms Fluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions
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