6. MONOAMINES IN DEPRESSION:
Serotonin,Norepineprine,Dopamine,
SEROTONIN:
• The CSF studies of patients with depression reveal a decrease in the level of the
major serotonin metabolite 5- Hydroxy Indole Acetic Acid(5-HIAA)
• Low CSF & cortical concentration of 5 HIAA also correlates with violent
suicides.
• Concentration of serotonin is significantly low in hypothalamus & amygdala of
depressed patients.
• Chronic AD treatment leads to desensitization of 5HT1A autoreceptors and
release of serotonin
• Selective blockade of central 5HT1B autoreceptor also facilitates serotonin
neurotransmission.
• The adaptive upregulation of 5HT2A due to reduced synaptic serotonin in
depression.
• Serotonin regulates dopamine release ,via 5HT2C & 5HT3 receptors.
7. NOREPINEPHRINE:
Reduced hormone levels –Depression,poor memory,lack of energy,concentration &
motivation.
• Decreased urinary levels of MHPG,major metabolite of NE.
• NE reuptake transporter levels reduced in locus coeruleus.
• Increased density & affinity of α2-adrenoreceptors in frontal
cortex,hippocampus,amygdala & cerebellum of depressed suicide victims.
• Upregulation of β adrenorecptors is also implicated in depression & its
downregulation is a marker of antidepressant efficacy.
DOPAMINE:
Reduced levels cause fatigue,depression and loss of interest in life.
• Decrease in CSF levels of DA metabolite Homovanillic acid is observed in
depression.
• decreased dopamine-transporter-binding potential in striatum
• Increased D2-receptor binding potential in striatum.
• D2 blocker treatment causes depression in schizophrenia.
8. MONOAMINES IN SCHIZOPHRENIA:
Dopamine,Serotonin
DOPAMINE:
• The Dopamine hypothesis of schizophrenia suggests that :
hypoactive mesocortical dopaminergic system -negative and cognitive symptom
and a hyperactive mesolimbic dopamine system- positive symptom.
• There is consistent evidence for an increased level of DA & its metabolites in
post mortem brain studies.
• Inreased D2 receptor in the striatum of schizophrenics
• PET studies suggest increased D2 receptor binding in the brains of
schizophrenics.
SEROTONIN:
• Serotonin excess causes positive & negative symptoms in schizophrenia.
NOREPINEPHRINE:
• Anhedonia-the impaired capacity for emotional gratification & the decreased
ability to experience pleasure.
9. SOCIAL PHOBIA:
Social phobia is characterized by excessive,disproportionate fear & avoidance of
social situations.
SEROTONIN:
• Low levels of CSF 5-HIAA results in low social competence.
• Pharmacological studies show SRIs decrease avoidance behaviour & improve
social behaviour.
NOREPINEPHRINE:
• Autonomic hyperactivity in social anxiety-Norepinephrine dysregulation
• Decreased concentration of MHPG
DOPAMINE:
• SPECT study demonstrated decreased striatal DA reuptake site density.Thus
some evidence suggests dopaminergic dysfunction in social anxiety disorder.
10. POST TRAUMATIC STRESS DISORDER(PTSD):
NORADRENALINE:
• Elevated levels of epinephrine & norepinephrine in 24 hour urine sample
• Relative elevation of MHPG was also found in night time samples in PTSD.
SEROTONIN:
PTSD often show features of serotonin dysfunction like
impulsivity,aggression,depression,suicidal behaviour.
• Altered serotonin transmission may cause symptoms of PTSD such as
hypervigilance,increased startle,impulsivity &intrusive memories.
• There is evidence that mice lacking the 5-HT1A receptor have increased fear
response.
• Studies show SSRIs are more effective than SNRIs.
DOPAMINE:
• Though evidence suggests that exposure to stressors induces mesolimbic DA
release,it is not clear whether MLDA system is altered in PTSD.Only
peripheral marker evidence for DA dysfunction is increased urinary excretion of
DA & its metabolites.
11. OBSESSIVE COMPULSIVE DISORDER(OCD):
SEROTONIN:
• Dysregulation of serotonin is involved in the symptom formation of obsessions
and compulsions.
• Serotonergic drugs are more effective in treating OCD
• CSF levels of 5-HIAA & platelet serotonin concentrations also show a decrease
when given serotonergic drugs.
• 5-HT1D autoreceptor desensitization in the OFC is associated with
improvement in OC symptoms.
DOPAMINE:
• Human studies show an increase in compulsive movements with amphetamine
& cocaine worsens compulsive movements.The evidence therefore suggests
that excess dopaminergic transmission may be associated with compulsions
NOREPINEPHRINE:
• Less evidence
• Improvement in OC symptoms with clonidine use ,a drug which lowers the
amount of NE.
12. ALCOHOLISM:
DOPAMINE:
• DA is a substrate for drug related reward,drug related learning and
neuroadaptation.The drug of abuse stimulate the dopamine transmission in the
nucleus accumbens/ventral striatum & produce euphoria . Alcohol acts indirectly on
the MLDA pathway.
• Dopamine is an important,but not essential component of alcohol reinforcement.
• Acute alcohol intake- increases DA
Alcohol withdrawl-decreases DA in dependent individuals.
• Type 1 alcoholism is related to lower density of dopamine & decreased dopamine
transporter binding & due to this they are vulnerable to excessive consumption of
alcohol in an effort to compensate for their subnormal dopamine levels.
SEROTONIN:
• Reduced concentration of 5-HIAA in CSF of alcoholics.
• 5-HT1A receptor partial agonist like buspirone reduces ethanol consumption.
• 5 HT1B receptor activity produces alcohol intoxicating effects.
• 5-HT3 receptor blockade(Ondansetron) reduces dopamine activity & the rewarding
effect of alcohol.
NORADRENALINE:
• In alcoholics,lower level of noradrenergic neurotransmission.
13. SEROTONERGIC DRUGS:
• 5-HT1A: Buspirone,Ipsapirone (Partial agonist) in treating anxiety
,depression.
• 5-HT1B/1D:Sumatriptan,Naratriptan,Zolmitriptan(partial agonist ) in
treating migraine.
• 5-HT2A/2C:Atypical antipsychotics(antagonist) in treating
migraine,depression,schizophrenia.
• 5-HT3:Ondansetron,Memantine,Mirtazapine
DRUGS ACTING ON SERT are TCA,SSRI,SNRI.
D2 receptors :Conventional antipsychotics(Antagonist)
Important Receptors in Psychopharmacology
14. Monoamine hypothesis:
Patients with depression have depleted concentrations of serotonin, not
epinephrine and dopamine. Two primary lines of evidence led to development of
the monoamine hypothesis:
1)Reserpine is used in hypertensive vascular disease in 1950s. However, it
precipitated depression in some patients.
Reserpine was found to inhibit vesicular monoamine transporter & hence
depletes brain monoamines (serotonin & catecholamines)
2)In 1953, new anti TB compound - Iproniazid, a monoalkyl derivative of
isoniazid.
Side effects: euphoria, psycho stimulation, increased appetite, improved sleep.
In 1958, a systematic trial on patients with depression showed improvement in
70% of patients.
In 1958, used off label to treat patients suffering from MDD.
15. MONOAMINE OXIDASE:
• MAO is an enzyme that produces oxidative disamination of biogenic
amines (serotonin, dopamine, epinephrine, nor-epinephrine) and
sympathomimetic amines (tyramine, benzylamine).
• Two types:
16. • The ratio of MAO-A to MAO-B in the human brain is 25% : 75% whereas in
the liver,the ratio is 50% : 50%, in intestine 80% : 20% .
• Brain MAO-A must be inhibited for antidepressant efficacy.
• Research has shown that individuals with loss of function variant of MAO-A
gene predisposes them to violence & anti-social behavior.
• MAO-B is more potent for DA & acts in 5-HT & NA only at high concentration.
• MAO-B inhibition yields no anti-depressant results. But used in Parkinsonism
.
