Transcript Antidepressants Dr S Lynch 7th Feb 2014

Sean Lynch
Consultant Psychiatrist and Honorary
Associate Professor, University of
Exeter Medical School
Summary of Main Objectives for Session
Aims Today
 Awareness of antidepressant types, efficacy, activity and
adverse effects
 Basic awareness of transmitters implicated in depression.
 Novel antidepressants
 Examples of possible MCQ AND CASC type questions
How psychopharmacology comes into MRCPsych
exams
 Basic sciences
 EBM analysis of papers related to drug treatments
 CASC questions on treatment / treatment resistance
Suggested Background Reading and Resources
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Stahl – Pharmacology of Antidepressants
Maudsley Prescribing Guidelines
NICE guidelines for anxiety and depression
Gaskell series (College)
Recent BMJ and BJPsych/APT review articles
BAP website
RCPsych website (look for Psychopharmacology links)
ABPI
Reactions to stressful experiences
• Acute reactions - immediate and brief responses to sudden
intense stressors in a person who does not have other psychiatric
disorder at time
• Post-traumatic stress disorder - prolonged and
abnormal response to exceptionally intense stressful circumstances
• Adjustment disorder - more gradual and prolonged
response to stressful changes in a person’s life
• Depression?
Reactions to stressful experiences
• There are implications for mechanism of action
of antidepressants and effectiveness
• Will antidepressants alter an intact but activated
stress-response system?
• Will continued stress overcome the effectiveness
of antidepressants?
The ten leading causes of disability
worldwide (1990)
Disability adjusted life years
All causes
Unipolar major depression
Iron deficiency anaemia
Falls
Alcohol use
COPD
Bipolar disorder
Congenital anomalies
Osteoarthritis
Schizophrenia
Obsessive compulsive disorders
Total (millions)*
472.7
50.8
22.0
22.0
15.8
14.7
14.1
13.5
13.3
12.1
10.2
% of total
10.7
4.7
4.6
3.3
3.1
3.0
2.9
2.8
2.6
2.2
Murray & Lopez eds. The Global Burden of Disease. Harvard University Press, 1996
Depression
• Depressive disorders are common, prevalence
2-5% (5-10% primary care settings). It affects
around 121 million people worldwide (WHO)
• Associated with significant morbidity and
mortality. Recently the WHO have announced
it is likely to be the single cause for burden of
any disease by 2030 due to years lost of life or
through severe disability.
• More prevalent in developing countries
Depression
• Pathophysiology
– Structural, neurochemical changes in
hippocampus, frontal cortex
– once thought to be a result of neurotransmitter
deficiencies (e.g., NA, 5-HT)
– More recent evidence suggests reductions in
neurotrophic hormones and reduced neuronal
plasticity
Depression
• Multisystem disorder (e.g. endocrine, immune
changes, increased risk of some physical illnesses)?
• Dysregulation of stress-response system
• Alteration in environmental adaptation and learning
• Role of 5HT1a and 5HT2
• Role of NA, Dopamine
• More recent interest in NMDA and glutamate
Implications in depression
 Decision making capacity
 Ability to deal with stressful / threatening situations
 Learning
 Information processing
Possible changes in depression
5HT1a upregulation
5HT2 antagonism
ß adrenoceptor downregulation
Possible effects on dopamine
Possible effects on neuropeptides
Altered HPA / corticotrophin function
Effects on plasticity and neural growth
Other systems may have changes (glutamate,
cholinergic)
Receptor types
1. lonotropic receptors
Ion channels - permeable to Ca2+ , Na+ K+ Cl- Strong electrical response e.g.
GABA, Nicotinic Ach
2. Metabotropic receptors
Receptor signal via metabolism. Most are G-protein coupled receptors where
NT binds leading to activation of second messenger e.g.
CAMP - adenylyl cyclase
CGMP - guanylyl cyclase
Basics of Receptor mechanisms
D- D7
5HT1a,b,c
5HT2 a,b,c
5HT3
NA
ß
α
Blockade in Psychosis, augmentation in
mood, reward/addiction
Agonism in anxiety, depression,
antagonism in migraine
Antagonism in depression, psychosis?
Antagonism in anxiety, psychosis?
Blockade ?depression
Not fully understood ? partial agents
Inactivation of
Neurotransmitters
• Diffusion
• Enzymatic degradation
• Re-uptake
Antidepressant Mechanisms
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Reuptake inhibition
MAO inhibition
Receptor Antagonism
Receptor Antagonism
Novel
Neurotransmitters implicated in depression
1. Amino acids
 amino butyric acid – GABA
Glutamate
2. Amines - contain an amine group but no acid
5-Hydroxytryptamine (5-HT)
Dopamine (DA)
Noradrenaline (NA)
3. Peptides - small chains of amino acids
Neurokinins/ Substance P
Endogenous opioids
CCK
VIP
4. Acetyl Choline
Neurotransmitters implicated in depression
GABA - Inhibitory , possible effects in anxiety and stress regulation?
5-Hydroxytryptamine (5-HT)
Sleep, reward, pain, learning, sexual drive, aggression
Dopamine (DA)
Drive, motivation, energy,
Noradrenaline (NA)
Aggression, drive
Acetyl choline – memory, cognitive function, sleep?
Peptides
“Master switch” ? adaptation, learning
Opioids?
Glutamate
The problem of which theoretical
model of brain function to use
Neurotransmitters implicated in depression
Dopamine?
Glutamate
Acetylcholine
Serotonin
Noradrenaline
-Aminobutyric acid
(GABA)
Neuropeptides
Corticotrophins
Antidepressant Classes and
Interactions
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Tricyclics
SSRI
SNRI
MAOI
Novel – NASSA, Melatonin Modulation
Experimental
Effectiveness in depression
•
All antidepressants appear to be as effective in moderate
severity illness (outpatient level), we are not sure about in
different severities or subtypes of depression, however.
•
Previous response to one class does not necessarily predict
future response
•
In some patients response can occur in subsequent episodes
with different antidepressant classes
•
Antidepressants might differ in effectiveness in long-term
maintenance and relapse prevention
Effectiveness in depression
•
Highest in moderate severity - 60-80% in trials but high
placebo response (40-60%)
•
Lower in mild severity and also high placebo response
•
Lower in severe (?50+% but few good trials), however lower
placebo response
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Issues about what constitutes a response versus remission
•
Issues about placebo design and “unblinding” in RCTs
CURRENT ANTIDEPRESSANTS
SSRI's
 paroxetine
 fluoxetine and norfluoxetine
 sertraline
 fluvoxamine
 citalopram and escitalopram
 (Clomipramine)
Antidepressants
Selective serotonin reuptake inhibitors: SSRIs
• 1st line: citalopram, sertraline, fluoxetine, paroxetine ad
fluvoxamine
• Max effect 4-6 weeks
• Side effects: commonest GI side effects, headaches,
insomnia
• Few anticholinergic side effects
• Low cardiotoxicity so safer in overdose.
• Withdrawal effects; worse if stopped suddenly: nausea,
dizziness, agitation, insomnia
SSRI's
Differences in half-lives and dosage / schedules
Selectivity differs e.g., fluoxetine more noradrenergic than
citalopram.
Paroxetine has greater anticholinergic activity
Have activity on peripheral and central serotonin receptors e.g.
5HT1a, 5HT2 but also 5HT1b and 5HT3. Might have some activity
on NA receptors (but much weaker)
Down regulate 5HT2 and possible enhance 5HT1a
Can suppress REM
Some doubts expressed about efficacy in more severe depression
SSRIs
• Side Effects and Other Concerns
– Serotonin Syndrome
– Serotonin Withdrawal Syndrome
– SSRI-Induced Sexual Dysfunction
– Gastrointestinal Bleeding
– Effects in Pregnancy/Breast-Feeding
– Recent increases in reports of fetal
malformations
– Suicidality and aggression
Serotonin Syndrome
• Due to excess serotonin
• Can be due to SSRIs and other antidepressants
• Causes: overdose, drug combinations/interactions,
sometimes at normal doses
• Can be fatal
• Symptoms: Neurological (confusion, agitation,
coma), Neuromuscular (rigidity, tremors, myoclonus,
hyperreflexia), Autonomic (hyperthermia,
tachycardia, hyper/hypotension, GI upset)
TRICYCLIC ANTIDEPRESSANTS
Divided into “first” generation drugs (imipramine, amitriptyline)
and “second” and “third” generation drugs.
Came from developments of potential antipsychotic drugs
Sedative
“Neutral”
“Stimulating”
More noradrenergic
More serotonergic
amitriptyline, dothiepin
imipramine, lofepramine
protryptyline,
Desipramine
Clomipramine
This is defined by ratio of NA to 5HT reuptake inhibition e.g. around 40
times greater for clomipramine for 5HT
Reuptake inhibition is not their only possible mode of action i.e. antagonism
effects and effects on autoreceptors. Some have questioned whether
anticholinergic effects may be related to effectiveness.
Reputedly, held by some authorities to be more effective than other classes
in severe depression
TRICYCLIC ANTIDEPRESSANTS
As a group they are more “mixed” in monoamine activity than modern agents
e.g. closer ratio of noradrenaline / serotonin activity than NARIs or SSRIs
Main postulated action re-uptake inhibition, but have effects on 5HT1a, 5HT2
and NA ß receptors
Relatively little effect on dopamine
Have membrane stabilising effects
Anticholinergic, antiadrenergic and quinidine effects.
Cardiotoxicity possible.
Lower seizure threshold.
Act on all monoamines.
Effects on 5HT1a 5HT2, D2, H1 and α1 and α2
Muscarinic ACh activity
TCAs
• Adrenergic
- postural hypotension
• Anticholinergic - dry mouth, blurred vision, constipation
• Antihistaminic - sedation
• Other
Cardiovascular - tachycardia, blockade, arhythmias
Epileptic threshold
Weight gain
Sexual dysfunction
Tremor
Parkinsonian effects
TCAs
• Pharmacokinetics
well absorbed orally
long half-lives, metabolised in liver
can have active metabolites e.g. imipramine and
lofepramine
• Pharmacodynamic
Active metabolites
Calcium channel blockers?
Antihypertensives?
TRICYCLIC ANTIDEPRESSANTS
Protein binding can displace / effect availability of other bound-drugs
Can be interactions with other agents via cytochrome metabolism
CPY450 1A2 metabolises clomipramine and imipramine and can be potently
inhibited by fluovoxamine
CPY450 2D6 is involved in tricyclic metabolism and paroxetine and
fluvoxamine are most potent inhibitors, but citalopram and sertaline less
potent
Carbamazepine can induce CYP450
Dual Action Antidepressants
• Nefazodone
– 5-HT2 receptor antagonist and 5-HT/NA reuptake
blocker; chronic use down regulates NA/5-HT
receptors., α1 and α2 activity,
– Similar properties in trazadone
• Mirtazepine
– 5-HT2/5-HT3 receptor antagonist; potent
antihistamine, α2 antagonist
• Venlafaxine 5HT > NA reuptake
• Duloxetine 5-HT/NA reuptake blocker, mild DA activity
NA specific and “Dual Action” Drugs
NASSAs
SNRIs
NARIs
- mirtazepine
- venlafaxine
- reboxetine
SNRIs and NARIs thought to rely on reuptake inhibition.
Venlafaxine SSRI - like until higher dosage and then NA activity
more potent – side effects (SSRI) plus headache, tremor, changes
in blood pressure (higher dosage). Duloxetine NA and 5HT activity
from low doses, reportedly fewer pressor and cardiac risks.
NARI – dry mouth, blurred vision, sweatiness, sedation
Mirtazepine (like mianserin) does not rely on reuptake inhibition,
but has activity at 5HT and NA auto and presynaptic receptors
which regulate respective transmitter turnover. More sedative
NARIs
• Reboxetine
– first NARI specifically developed for
depression.
– improved attention and speed of cognitive
functioning
MONOAMINE OXIDASE INHIBITORS
Serendipitous find in TB treatment (isoniazid, iproniazid)
Irreversible and non-selective (for MAO subtype)
Phenelzine (Hydrazine)
Tranylcypromine (non-hydrazine) – more potent inhibitor
Reversible and selective
Moclobemide
Brofaromine
reversible (MAOA)
- some weak MAOB activity,not therapeutically significant
Selegiline
reversible MAOB – weak MAOA activity, little antidepressant
activity
Adverse effects similar to tricyclics but non-sedative. ? addiction syndrome for some
older MAOIs. Cheese reaction, drug interaction, hepatotoxicity,
neurotoxicity Fewer adverse effects for moclobemide
? Differential effects on dopamine turnover viz a viz other antidepressant
classes
Now “second-line”, less effective than other classes (except atypical
depression?)
MAOIs
• Pharmacology
– Inhibition of monoamine oxidase
– MAO-A (depression) MAO-B (Parkinsons)
• Side Effects
– potentially serious interactions with adrenergic drugs
some anaesthetics and opiates.
• Recent advances
– Transdermal delivery of selegiline
MAOIs
• Monoamine oxidase inhibitors
• Isocarboxazid, Phenelzine
• “Cheese reaction”: tyramine rich food can
cause a hypertensive crisis: need to avoid
foods rich in tyramine e.g. cheese, red wine,
liver, yeast products.
• RIMA: moclobemide
Have we made any progress
with antidepressants?
Future Antidepressants?
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Buspirone group
Tianeptine
Omega-3 Fatty Acids
NK1 antagonists
DHEA (glucocorticoid hormone) or modulators
Glutamate modulators? (Recent trial of IV
ketamine, rapid and sustained effects in TRD)
Antidepressant Effectiveness
• Efficacy
• Clinical Effectiveness
• Safety and Adverse Outcomes
Clinical Effectiveness
Drug Efficacy depends upon:
• pharmacology,
• pharmacodynamics,
• pharmacogenetics
Clinical Effectiveness depends upon:
• efficacy,
• tolerability,
• adherence
SHOULD WE ALWAYS USE NEW DRUGS?
Ethical and practical issues
 Efficacy vs effectiveness
 Costs of treatment
 Toxicity of treatment
 Disease delayed or modified?
Antidepressant activity - evidence based?
1.Success rate of treatment for episode
• Severity of episode
 Dosage
 Compliance
 Duration
2. Effects on illness duration, risk of relapse and risk of recurrence
• Symptomatic
 Shorten episode
 Some prophylactic effects
 Hard to know who should take these and for how long i.e markers, how big
the effect
 Little scientific evidence regarding predictors of relapse or recurrence
Antidepressant activity - evidence based?
3. Basic properties of antidepressants
 All equally effective in moderate illness
 Similar lag phase before therapeutic activity
 Differential responses occur
 May not all be as effective in different types of depression, OCD,
anxiety disorders
•
Antidepressant withdrawal syndromes
 Documented for all antidepressants
 Usually just physiological adaptation
 Some have psychological dependence (MAOI’s)
 Some produce EPS
Antidepressants - safe?
Discontinuation symptoms / syndrome
Suicidality
Aggression - “the Prozac Defence”
Treatment resistance
“Switching”
Antidepressant activity - evidence based?
Antidepressant augmentation
 Evidence for Li, L-tryptophan
 Less evidence for T3, anticonvulsants
Treatment resistance
The basic principles are similar to those for any treatment resistance.
• Is diagnosis correct?
• Is drug treatment dose optimum? Compliance, pharmacokinetics,
pharmacodynamics
• Has drug been given for right period?
• High dosage regimens can be used with TDM and regular safety monitoring
• Rate response on recognised scale
• Change to a different antidepressant class (some debate about this and some
suggest second drug within same class e.g. if SSRI and then change)
• Some patients respond with any switch (?placebo response)
• Augmentation therapy:- Lithium, L-tryptophan
• Cocktail approach - little firm evidence they are helpful.
Drug-related poisoning deaths, England & Wales, 1993 to 2000
21,631 drug-related poisoning deaths
50% of these suicides
3,959 - deaths which mention
antidepressants
79% of these suicides
49
Trends in antidepressant-related deaths, England & Wales, 1993
to 2000
Numbers of deaths
600
500
400
Other
antidepressants
Amitriptyline
300
200
Dothiepin
100
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
0
Year of death
50
Deaths per million population
Antidepressant-related age-specific death rates, England &
Wales, 1993 to 2000
20
18
16
14
12
10
8
6
4
2
0
Male
Female
0-14
15-29
30-44
45-59
60-74 75 and All
over ages
Age group
51
See you back in twenty minutes
ANTIDEPRESSANT DRUGS
CLINICAL PROBLEM
A 46 year old woman has an 8 week history of poor sleep, weight
loss and reduced social contact. She has not complained of
depressed mood, however. She is menopausal and has peptic
ulcer disease and has recently started treatment for high
cholesterol. Two weeks ago her G.P. started her on paroxetine. Her
sleep and appetite have not improved and she has become
restless. Her medication is shown overleaf.
Discuss the appropriateness of the medication.
Why could the drug have had this effect?
Would you change this and if so why?
ANTIDEPRESSANT DRUGS
CLINICAL PROBLEM ONE
Temazepam
Paroxetine
20mg
20mg
She is also taking:Omeprazole
Simvastatin
Evening Primrose Oil
Chinese Herbal Medicine
Multivitamins
Premarin (Equine conjugated oestrogens)
ANTIDEPRESSANT DRUGS
CLINICAL PROBLEM TWO
A 44 year old man has a long history of generalised motor seizures
which have been well-controlled. He has a 5 week history of
low mood, lack of energy, sleep disturbance with early morning
wakening, poor concentration and pessimistic thoughts. He has
tried dothiepin (dosulepin) but developed excessive sedation and
had possible petit mal seizures.He tried fluoxetine which was not
effective and also caused sedation. He is currently taking
venlafaxine at a dosage of 225mg daily. He also takes warfarin for
a previous deep venous thrombosis.He is complaining of stomach
upset and diarrhoea.
Discuss the appropriateness of the medication.
Why could the drug have had this effect?
Would you change this and if so why?
ANTIDEPRESSANT DRUGS
CLINICAL PROBLEM TWO
Warfarin
(variable as per clinic card)
Carbamazepine
Sodium Valproate
400mg tds
200mg qds
He is also taking:Multivitamins
Problems
1. A 50 year old woman with depressive illness has been taking
fluoxetine but noticed increasing tiredness and nausea and a
deterioration in her mood. It comes to light that she has been
taking a mixture of natural herbal medicines for depression in
addition. Discuss the importance of this new information using
psychopharmacological principles.
2. A 39 year old man with depressive illness has had olanzapine
added to his sertraline antidepressant. After 8 days treatment his
symptoms worsen. Discuss why this might have occurred.
NOW FOR SOME PRACTICE MCQs!!!
RECAP OF FUNCTION
OF MAIN TYPES OF
NEUROTRANSMITTER
READING /REVISION OUTSIDE
OF LECTURE
Amino Acids
Glutamate
Synthesised in 50% of synapses
•Most important CNS excitatory neurotransmitter
•Neurotoxicity
•Major efferent transmitter from cerebral cortex to
basal ganglia, thalamus, limbic system
•Both receptor subtypes i.e. metabotropic and
ionotropic glutamate receptors
Inotropic glutamate receptors - N-methyl-D-aspartate
(NMDA)
Distribution of NMDA receptors. NR2A - throughout
brain. NR2B – Striatum. NR2C - cerebellum involved in
•Neuronal plasticity - learning and memory
•Development of the CNS
•Anaesthesia
Activation of NMDA implicated in pathological states as
excess glutamate activation  messengers 
increased Ca2+  neuronal death
Stroke, head injury, epilepsy, Parkinson's disease excitotoxicity. Possible therapeutic effects of NMDA
receptor antagonists? Depression ? Schizophrenia e.g.
PCP-induced psychosis
GABA
Predominant inhibitory neurotransmitter in the brain
and spinal cord - 30 % synapses utilise GABA
•GABA removal is via a high affinity transporter.
•Modulate and control flow of sensory information
•Interneurons - within all CNS structures e.g. stellate
cells in cochlear
•Striatal projection neurons to the globus pallidus and
substantia nigra
•One brain structure may receive many GABAergic
inputs from different structures
GABA receptors
GABAA receptor
Ion channel selective for Cl-. GABA binding leads to activation of
the channel,and hyperpolarisation
Barbiturates Benzodiazepines - binds to  subunit
Agonists – Muscimol, Picrotoxin
Antagonists - Bicuculline, Flumazenil (BZ site), Penicillin - blocks
open channel
GABAB receptors
G-protein coupled. Inhibit CAMP
Increase K - inhibitory post synaptic potential. Decrease Ca flux
Pre and post synaptic.Pre - inhibit NT release
Agonists Baclofen
Glycine
Inhibitory NT. Co-expressed with GABA and coreleased
•Found in spinal Cord Renshaw cells (+ GABA) and
la inhibitory interneurons.
•Recurrent and reciprocal inhibition of spinal motor
neurons
•Auditory and cerebellum. Cochlear -large glycine
input
•Forebrain -coagonist at NMDA receptor
Acetylcholine
Widely distributed and found at following sites:Neuromuscular junction
Sympathetic and parasympathetic preganglionic
Parasympathetic post ganglionic
•CNS
Acetylcholine receptors
• Nicotinic – NMJ and also present within the CNS
• Muscarinic - Ml, M2, M3, M4, M5
Ml - cortex
M2 - thalamus, hypothalamus
M3 - limbic cortex, striatum, hippocampus,
M4 - striatum
M5 mRNA only - Substantia nigra and VTA
•Excitatory - suppress inward currents e.g. K+ currents,
facilitates NMDA responses
•Inhibitory - increase K+ conductance e.g. vagal
inhibition of heart and few sites in the CNS e.g.
thalamus and brain stem
Function of cholinergic system
•Cognition
Reduced cholinergic activity in dementia. Loss of neurons in nucleus basalis.
Cell loss correlates with dementia in PD. Decrease in choline
acetyltransferase actvitly and upregulation of ACh receptors in cortex.
Decreased M2 receptor pre synaptic and increased M4 receptors -post
synaptic. Anticholinergic agents cause confusion
Mood regulation (reciprocal relationship with monoamines or
modulator???)
•Movement/Tremor/dystonia
•Interaction with dopamine receptors:Dopamine D1 receptors stimulate ACh release and Dopamine D2 receptors
inhibit ACh release. Dopamine D2 receptor antagonists e.g. anti-psychotics,
anti-emetics cause acute dystonia
Biogenic amines
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Dopamine, 5-HT, NA, A
Functions:Cortical- behaviour, mood, perception
Subcortical- Basic functions sleep,
appetite and motor
EMOTIONAL
RESPONSE
STRESS RESPONSE
Serotonin
5-HT function in the brain
•Sleep-wake cycle and level of arousal e.g. in R.E.M.
sleep there is little activity of serotonergic neurons in
the DRN (dorsal raphe nucleus), but maximal
discharge during arousal
•Satiety. Feeding increases 5-HT levels in the lateral
hypothalamus of the rat.
•Regulation of anterior pituitary hormone control,
growth hormone, prolactin and corticotrophin
APPETITE CONTROL
Serotonin receptors
Classification based on receptor structure,
transduction mechanisms and pharmacology
All G-protein coupled except 5-HT3
5-HT1 family - 5-HTlA, 5-HTlB, 5-HTlD, 5-HT1E 5-HT1F
5-HT2 family – 5-HT2A , 5-HT2B , 5-HT2C
5-HT3 ,
5-HT4,
5-HT5 family- 5-HT5A ,5-HT5B
5-HT6
5-HT7
PLEASURE RESPONSE
The 5-HT1 receptor family
5-HT1A,B,D,E and F coupled to adenylyl cyclase.
Autoreceptors - control of 5-HT, or other NT release.
•5-HT1A receptor:- limbic system, amygdala, septum and
hippocampus. 5-HT cell bodies within the DRN and inhibits
5-HT release and cell firing. Effect mood and emotion.
•5-HT1B and 5-HTlD receptors distributed in hippocampus,
cortex and pre-synaptically on the striatal projections
5-HT1B important in controlling 5-HT release and release of
acetylcholine, glutamate and dopamine. Reduced sensitivity
and 5-HT levels in alcoholism shown in man. SSRI's use in
alcoholism mediated via 5-HTlB
The 5-HT2 receptor family
5-HT2A receptor- widely distributed in the brain and periphery, cortex, limbic system,
caudate.
•Hallucinatory properties of the 5-HT2A agonist, LSD. Mixed dopamine D2/5-HT2A antagonist
clozapine used in schizophrenia.
•A decrease in 5-HT2A receptor numbers in the frontal cortex of schizophrenic patients.
•Anti-psychotic effects via action within the GABAergic interneurons in the cortex.
•Decreases in the level of 5-HT and 5-HIAA and compensatory increase in 5-HT2 binding in
ventral prefrontal cortex of violent suicide victims
5-HT2B receptor:- Wide peripheral distribution. Animal studies have suggested roles in
anxiety
5-HT2C receptor:- Located exclusively within the CNS, highest levels in the choroid plexus.
Agonist, 1-(3-chlorophenyl) piperazine (MCPP) - induced anxiety in humans.
•Obsessive-compulsive disorders: two newly developed, selective 5-HT2C agonists reduce
behviour in animal models
•Satiety - Weight loss - mCPP-induced hypophagia. SSRI's.
Other 5-HT receptors
5-HT3 receptor:- In lower brain stem, cortex, hippocampus, amygdala. sensory and
autonomic nervous system.
•Vasodilatation
•Pain
•5-HT3 receptor antagonists ?anxiolytic and antagonist ondansetron effective in
treating some psychotic symptoms?
5-HT4 receptor
anxiety ? altering 5-HT release in the hippocampus
5HT6 - possibly in striatum, high affinity for typical and atypical neuroleptic drugs