psychopharmacology and serotonin

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                                 The role of Serotonin

                                              Dr. Craig Jackson
                          Senior Lecturer in Health Psychology

                                               Faculty of Health
Depressive Illness

Usually treatable
        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”

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”

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
 reactive episodes

Major Depressive Disorder (MDD)
 5 symptoms displayed in 14 days

 depressed mood for 2+ years
 not severe
 chronic depression
 unhealthy lifestyle associations

Bipolar Disorder / manic depression
major depression & mania
Classification of Depression (ICD-10)

              Mixed anxiety and depressive disorder (prominent anxiety)
              Depressive episode (single episode)
              Recurrent depressive disorder (recurrent episodes)
              Dysthymia - Persistent and mild ("depressive personality")
             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...
               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

• 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

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

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

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




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
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        n=15
                                            Suicidal History            n=9
              5-HIAA ng/ml
              20    00 40

                             0   4   8       12      16       20   24

                                         Total Aggression Score

Brown et al. 1979
Psychopathology of Disruptive Behaviour Disorders

             Trauma Related Disorders             Personality 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-HT2A 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


          Chronic MDMA user
Serotonin Hypothesis

Pre-Synaptic 5-HT output reduced

Post-Synaptic receptor sensitivity increased
Serotonin Pathway
Serotonin Neurotransmission

Centrally active drug

Benzeneethanamine, N-ethyl-alpha-methyl-3

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

Central Nervous System Stimulant

Similar to Dextroamphetamine

Benzeneethanamine, alpha, alpha-dimethyl

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     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
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,    (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.
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

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

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

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

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