This document discusses various types of major affective disorders including major depression, bipolar disorder, seasonal affective disorder, and mania. It provides classifications and descriptions of these disorders and covers their core symptoms. The document also discusses various biological factors and theories related to these disorders such as changes in neurotransmitter levels and genetic components. Finally, it examines several classes of antidepressant medications including TCAs, MAOIs, SSRIs, and atypical antidepressants. It describes the mechanisms of action and side effects of these different drug classes.
2. Classification of Major Affective Disorders
M a jo r A ffe c tiv e
D is o rd e rs
E p is o d a l
D e p re s s io n
M a jo r/
Endogenous
D e p re s s io n
M a n ia
Seasonal
A ffe c tiv e
D is o rd e r
A ty p ic a l
D e p re s s io n
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B ip o la r
d e p re s s io n
4. Reactive (episodal) Depression
♦More than 60% of all depressions.
♦Core depressive syndrome: feelings
of misery, apathy, inadequacy,
pessimism, anxiety, tension, guilt.
♦Bodily complaints
♦May respond spontaneously or to a
variety of administrations.
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5. Major Endogenous Depression
• Recurrent, Cyclic, Seasonal.
• Degree of depression is not adequate
for precipitating event.
• Automaton (unresponsive).
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6. Major Endogenous Depression
Core Symptoms:
• Feeling of misery, apathy and pessimism.
• Withdrawn.
• Low self –esteem, feelings of guilt, inadequacy and
ugliness.
• Loss of interest in pleasurable activities.
• Indecisiveness, loss of motivation.
• Retardation of thought and action. Sleep
disturbance and significant weight change (without
dieting or changes in appetite).
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• Psychomotor agitation or retardation.
7. Major Endogenous Depression
Core Symptoms (con’t):
• In severe cases, it is accompanied by
hallucinations and delusions.
• Recurrent suicidal ideation, a suicide attempt or a
specific suicide plan.
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8. Mania
• Mania alone is rare (10%) and most frequently
cycles with Major/endogenous depression (ManicDepressive Disease, Bipolar Disorder).
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9. Mania
Core Symptoms:
• It is characterized by an elevated “high” mood.
• Talkative, go on-and-on about the things they will
do.
• Increased self-esteem.
• Auditory hallucinations.
• Decrease need to sleep.
• Lack judgement, indiscrete.
• SuperME
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10. III. Biological Correlates of
Depression
1. Hypersecretion of cortisol.
2. Escape from dexamethasone suppression.
3. Blunted TSH response to TRH.
4. Blunted GH response to hypoglycemia.
5. Altered 24hr rhythm of prolactin secretion.
6. Decreased 5-HT metabolites in plasma.
7. Decreased REM latency.
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11. IV. Biological Basis for Depression
1. Has a genetic component.
2. Depression can be drug-induced.
3. Depression can be drug-repressed.
4. Depression can be treated with drugs.
5. Depression can be treated with
Electroconvulsive Therapy (ECT).
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12. V. Biogenic Theory of Depression
• The precise cause of affective disorders
remains elusive.
• Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
the CNS, Norepinephrine (NE) and
Serotonin (5-HT).
↓ Activity of NE and 5 -HT systems?.
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13. VI. NE System
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas (hippocampus, amygdala,
hypothalamus, thalamus).
• Mood: -- higher functions performed by the
cortex.
• Cognitive function: -- function of cortex.
• Drive and motivation: -- function of brainstem
• Memory and emotion: -- function of the
hippocampus and amygdala.
• Endocrine response: -- function of hypothalamus.
α and β receptors.ww.indiandentalacademy.com
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14. VII. Serotonin System
As with the NE system, serotonin neurons located
in the pons and midbrain (in groups known as
raphe nuclei) send their projections diffusely to the
cortex, hippocampus, amygdala, hypothalamus,
thalamus, etc. --same areas implicated in
depression. This system is also involve in:
•
•
•
•
•
•
Anxiety.
Sleep.
Sexual behavior.
Rhythms (Suprachiasmatic nucleus).
Temperature regulation.
CSF production.
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15. Antidepressants
S S R Is
TCAs
s
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V
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axine
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SSR
Venflaxine
Is
SSR
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dox
SSRIs TC
TCAs
epi
MAOIs
As
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Is
MAO
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Is
A
TCAs
M
MAOIs
ide
az Is
box O TCAs
car
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MAOIs
maprotiline
MAOIs
MAOIs SSRIs
Am
ox
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Venflaxine
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e MAOIs
rtriptylin
No
17. Mechanism of Action
1. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
2. Inhibition of MAO enzymes.
(MAOIs).
3. 5-HT2A and 5-HT2C antagonists.
(Nefazodone, trazodone, mirtazapine)
4. Alteration of NE output .
(Bupropion)
5. Stimulation of 5-HT1A receptors.
(
6. α2–AR antagonists.
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(mirtazapine)
19. Tricyclic Antidepressants (TCAs)
• Characteristic three ring nucleus.
• Most are incompletely absorbed, all are
metabolized in liver => High first pass effect:
1) Transformation of the tricyclic nucleus
=> hydroxylation => conjugation =>
glucoronides.
2) Alteration of aliphatic side chain =>
demethylation of the nitrogen => active
metabolites.
• High protein binding, high lipid solubility.
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22. Tricyclic Antidepressants (TCAs)
Mechanism of Action:
- Inhibition of NT reuptake.
- Immediate action = >↑ NE and 5-HT in synapse.
- After chronic treatment (2 - 4 weeks) = >
↓ β NE-R and ↓5-HT2R.
↓ NE release and turnover.
↓ NE-stimulated cAMP in brain.
↑ Sensitization of 5-HT receptors.
* Adaptive Responses *
- Takes up to 4 weeks for all TCA antidepressants to
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23. Tricyclic Antidepressants (TCAs)
Side Effects:
• Atropine-like side effects: dry mouth,
paradoxical excessive perspiration,
constipation, blurred vision, mydriasis,
metallic taste, urine retention => muscarinic
blockade.
• Orthostatic hypotension => α1-AR and
possibly α2-AR blockade.
• Drowsiness, sedation and weight gain =>
Histamine-Receptor blockade.
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24. Tricyclic Antidepressants (TCAs)
Side Effects (con’t):
• Most serious side effect is cardiac toxicity
=> Palpitations, tachycardia, dizziness =>
excessive CNS stimulation => ↑NE in Heart.
• Sexual dysfunction, including loss of libido,
impaired erection and ejaculation and
anorgasmia
. …↓ COMPLIANCE
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25. Tricyclic Antidepressants (TCAs)
Other effects (con’t):
• Metabolism is affected by: Smoking, Barbs,
estrogens, neuroleptics and anticonvulsants.
• Can lower seizure threshold.
• All TCAs can cause: vagal block, postural
hypotension, arrythmias, sinus tachycardia.
• All potentiate CNS depressants (BZDs, Barbs,
ETOH) => coma and death.
• TCA administration in bipolar disorder may
precipitate acute mania or rapid cycling.
• Fatal in overdosewww.indiandentalacademy.com can kill anyone).
(a 2 wk supply
27. X. MAO INHIBITORS
• Developed for the treatment of tuberculosis
(iproniazid derivatives) - 1951.
• These drugs are not widely used today, although
a small number of patients appear to do better in
MAOIs than TCAs or the newer drugs.
• Are readily absorbed from GI tract and widely
distributed throughout the body.
• May have active metabolites, inactivated by
acetylation.
• Effects persist even after these drugs are no
longer detectable in plasma (1-3 weeks).
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28. X. MAO INHIBITORS
Mechanism of action:
Inhibit MAO enzymes (non-selective):
1) Irreversible MAO inhibitors
Phenelzine and isocarboxazid => hydrazides.
2) Reversible MAO Inhibitors.
Tranylcypromine => non-hydrazide,
prolonged blockade, but reversible within 4hr.
Decrease metabolism of most biogenic amines
(NE, 5HT, DA, www.indiandentalacademy.com
tyramine, octopamine).
29. X. MAO INHIBITORS
Mechanism of action (con’t):
Acute administration causes:
↑ NE and 5-HT in synaptic terminals in brain but
↓NE in PNS. ↓NE synthesis.
– Acute euphoria
– Suppressed REM sleep.
Chronic administration causes:
↓ NE-stimulated cAMP in brain.
– Down regulation of β receptors.
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– Down regulation of 5-HT2 receptors.
30. X. MAO INHIBITORS
MAO-A NE, 5-HT, Tyramine
MAO-B DA
Selective MAOIs:
Inhibitors MAO-A
Moclobemide, Clorgyline
Inhibitors of MAO-B.
Deprenyl, Selegiline
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31. X. MAO INHIBITORS
Wine-and-Cheese Reaction
- Fatal interaction with tyraminecontaining foods (fermented foods in
particular, such as wine and cheese).
- ↓ MAO-A => ↑ Tyramine in the body
=>↑NE in circulation => induces
hypertensive crisis => can lead to
intracranial bleeding and other organ
damage.
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32. X. MAO INHIBITORS
Negative drug interactions with:
Any drug metabolized by MAOs* including
SSRIs, TCAs and meperidine, alcohol, CNS
depressants, sympathomimetics,
phenylephrine (O/C nasal decongestants),
ampetamines, and other indirect-acting
adrenergic drugs.
*
Interaction with drugs metabolized by MAOs (e.g.
Meperidine (opioid analgesics) => hyperpyrexia or
“hyperexcitation syndrome” involving high fever,
delirium and hypertension).
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33. X. MAO INHIBITORS
Other side effects:
• Hypotension
• Hepatotoxicity.
• Sedation.
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34. XI. SSRIs
• Fluoxetine
• Sertraline
• Paroxetine
• Fluvoxamine
(Labeled for obsessive-compulsive disorder)
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35. XI. SSRIs
• Most widely prescribed drugs for
depression.
• They have few side effects and seem to be
rather safe. More rational prescribing and
better patient compliance.
• Adverse effects include: nausea, decreased
libido, decrease sexual function.
• Low threat for overdose. Suicide may be
considered in severe depression.
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36. XI. SSRIs
Mechanism of action:
• Specific serotonin uptake inhibitors increase
5-HT by inhibiting reuptake.
Current theory holds that:
• Enhanced stimulation or responsiveness of
postsynaptic 5-HT1A receptors is particularly
important in the action of antidepressants.
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37. XI. SSRIs
Fluoxetine is the prototype.
• Approximately 70% of depressed patients will
respond to an SSRI therapy at the end of 6 weeks
(4 to 6 weeks before effects are evident to patient).
• T1/2 of 16 – 24 hrs. except for fluoxetine’s metabolite
norfluoxetine (T1/2 = 8 days).
• Fluoxetine and paroxetine inhibit liver enzymes,
particularly P450-2D6.
• Paroxetine and Sertraline have PK parameters
similar to TCAs.
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38. XI. SSRIs
Drug-drug interactions:
dangerous with other antidepressant drugs,
MAOIs in particular.
”Serotonin Syndrome”:
– hyperthermia, muscle rigidity, myoclonus, rapid
changes in mental status and vital signs.
Thus it is important to wait up to 6 weeks after
medication is stopped, before starting with another
drug.
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40. XII. Heterocyclics
• The second and third generation antidepressants
are by no means a homogeneous group.
• As with the TCA's , they all have variable
bioavailability.
• High protein binding.
• Some have active metabolites.
• Trazodone and Venlafaxine have the shortest
plasma half-lives, which mandates divided doses
during the day.
• Nefazodone and fluvoxamine cause inhibition of
CYP3A4.
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41. XII. Heterocyclics
Mechanism of Action:
1) NT reuptake inhibition.
maprotiline.
2) 5-HT receptor antagonism (for 5-HT2A or
2C receptors).
nefazodone, mirtazapine, and
trazodone
3) Alteration of NE Output.
bupropion, amoxapine, and trazodone.
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42. XII. Heterocyclics
Amoxapine. Metabolite of Loxapine (an antipsychotic) -- retains some antipsychotic
activity and DA receptor antagonism =>
parkinson's-like symptoms. May be useful
if psychosis is present. NE output.
Maprotiline. A tetracyclic drug, resembles
desipramine with less sedative and
antimuscarinic side effects. Evokes
seizures at high doses. Blocks NT
reuptake.
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43. XII. Heterocyclics
Trazodone. Antagonist of 5-HT2A or 2C receptors.
Unpredictable efficacy. Highly sedative
(hypnotic), but minimal antimuscarinic
action.
Bupropion. Resembles amphetamine. Blocks
DA reuptake (not important in depression).
Causes CNS stimulation. Inhibits appetite.
Aggravates psychosis. NE output.
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44. XII. Heterocyclics
Third Generation
Mirtazapine. A derivative of mianserin. Antagonist of
5-HT2A or 5-HT2C receptors. Also antagonizes α 2adrenergic receptors, thus increasing NE and 5-HT
release. Very sedating.
Venlafaxine. Short plasma half-live, thus needs to
be given in divided doses. Potent inhibitor of 5-HT
uptake and weaker at NE reuptake (at low
concentrations it acts like an SSRI).
Nefazodone. Antagonist of 5-HT2A or 5-HT2C
receptors. Moderately sedating. Potent inhibitor of
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CYP3A4, so cannot be given with cisapride
45. XII. Atypical/Heterocyclic
2nd Generation heterocyclics
• Amoxapine
Similar to TCAs
⇑NE output
• Maprotiline
α2-AR antagonist
• Trazodone
5-HT antagonists
• Bupropion
SSRI-like
Third Generation heterocyclics
• Mirtazapine
• Venlafaxine
• Nefazodone
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46. Noradrenergic Control of Serotonergic Release
Receptors
α 2-AR
NE
5-HT
α 1-AR
5-HT1
5-HT2
5-HT3
NE
1
2
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3
Mianserin
47. XIV. Alternative Therapies
No way of a priori knowing which therapy
will be best for a patient.
•
•
•
•
Light Therapy
Psychological Treatment
ECT
St. John’s Wort
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51. XVI. Anti-Manic Drugs
Lithium (Li+) remains the drug of choice for the
treatment and prophylaxis of mania.
• Acute manic episodes are managed with lithium
salts (carbonate or citrate) alone, or in combination
with:
1) Antipsychotics (carbamazepine, similar in
structure to TCAs but not effective in
depression).
2) Valproic acid
3) Calcium-channel blockers (nifendipine,
diltiazem, verapamil).
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52. XVI. Anti-Manic Drugs
+
Li
• Small monovalent cation (between H+ and
Na+).
• Distributed in total body water, similar to
sodium.
• May partially inhibit Na+-K+ ATPase.
• Inhibits ADH => diuresis.
• May decrease thyroid function.
• Teratogenic (tricuspid valve malformation).
• Excreted by kidney.
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53. XVI. Anti-Manic Drugs
+
Li
• Not to be taken with thiazide diuretics (e.g.
chlorthiazide).
• Lithium clearance is reduced by 25%.
• All neuroleptics (with the exception of
clozapine), produce more severe
extrapyramidal syndromes when combined
with lithium.
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54. XVI. Anti-Manic Drugs
+
Li
• Helps alleviate the depressive phase of
bipolar illness.
• Useful in refractory depression when
added to SSRIs or TCAs, but not a good
antidepressant alone.
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55. XVI. Anti-Manic Drugs
Li
+
Mechanism of action:
• Does not alter receptor numbers but alters the
coupling of the receptors with their second
messengers by reducing coupling of G-proteins.
• Regulation of β-AR and DAR.
• Can reduce release of NTs (5-HT) and affinity of
binding to receptor.
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56. XVI. Anti-Manic Drugs
Li
+
Mechanism of action (Con’t):
Inhibits breakdown of IP2 to IP1 (during PIP
hydrolysis) => depletion of DAG and IP3 and ↓
[Ca2+] in response to receptor activation (i.e.
from 5-HT2R, α1-AR, muscarinic receptors and
others).
• Alterations in adenylate cyclase and
phospholipase C.
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58. XVI. Anti-Manic Drugs
Valproic Acid
A well known antiepileptic has been found to
have antimanic effects. Shows efficacy
equivalent as that of lithium during the early
weeks of treatment and is being evaluated for
maintenance treatment. Titrated well, the
sedation can be controlled. Nausea being the
only limiting factor in some patients.
May be used as first line treatment for mania,
although it may not be as effective in
maintenance treatment as lithium for some
patients.
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Mechanism of action: ???
59. XVI. Anti-Manic Drugs
Carbamazepine
Effective as an antimania medication
Mechanism of action (Con’t):
May be due to decrease overexcitability of
neurons (anticonvulsive effect).
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60. XVI. Anti-Manic Drugs
Ca2+ Channel blockers
Nifedeipine
Verapamil
Mechanism of action (Con’t):
NT Release?
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High correlation particularly among kin
Reserpine, a drug used in the treatment o hypertension and schizophrenia can cause depression because it depletes the vesicular storage of amine neurotransmitters (NE, 5-HT, DA).
Depression could be relieved by isoniazid, a drug used in the treatment of tuberculosis.
TCAs, MAOIs, SSRIs, and all the new drugs.
ECT causes a massive release of NTs and is a very effective antidepressant.