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Episodal
Depression
Seasonal
Affective
Disorder
Atypical
Depression
Major/
Endogenous
Depression
Mania
Bipolar
depression
Mania
Mania alone is rare (10%) and frequently cycles with Major/endogenous
depression
Manic--Depressive Psychosis, Bipolar Disorder
Manic
Core Symptoms:
Elevated high mood.
Talkative, go onon-and
and--on about the things they will do.
Increased selfself-esteem
Auditory hallucinations
Decreased need to sleep
Lack of judgment, indiscrete
Super ME
NE System
Almost all NE pathways in brain originate from cell bodies
of neuronal cells in locus coereleus in the midbrain
They send their axons diffusely to the cortex, cerebellum
and limbic areas (hippocampus, amygdala, hypothalamus,
thalamus)..
thalamus)
Mood: higher functions performed by the cortex
Cognitive function: function of cortex
Drive and motivation:
motivation: function of brainstem
Memory and emotion:
emotion: function of the
hippocampus and amygdala
Endocrine response:
response: function of hypothalamus
Serotonin System
As with NE system, serotonin neurons located in pons
and midbrain (raphe nuclei) send their projections diffusely
to the cortex, hippocampus, amygdala, hypothalamus,
thalamus
Same areas implicated in depression
This system is also involved in:
in:
Anxiety
Sleep
Sexual behavior
Rhythms (Suprachiasmatic nucleus)
Temperature regulation
CSF production
Antidepressants
1. Tricyclic antianti-depressants (TCAs)
Imipramine, desipramine, nortriptyline,
nortriptyline,
protryptyline,, amytriptiline, doxepin
protryptyline
2. Monoamine oxidase inhibitors (MAOIs)
isocarboxacid, phenelzine, tranylcypromine
3. Selective serotonin reuptake inhibitors (SSRIs)
fluoxetine, sertraline, paroxetine
4. Atypical antianti-depressants (Others)
amoxapine, bupropion, maprotiline,
nomifensine, mianserin, venlafaxine, trazadone
3Amines
Amines::
2Amines:
Selectivity
Imipramine, Amitriptyline
Desipramine, Nortriptyline
2o Amines -- NE > 5-HT
3o Amines
Amines--- 5-HT > NE
TCA - ADR
Dry mouth, constipation, blurred vision, urinary retention muscarinic blockade
Orthostatic hypotension - 1 blockade
Drowsiness, sedation and weight gain - Histamine
Histamine-Receptor blockade
Palpitations, dizziness - NE in Heart
Sexual dysfunction & loss of libido
MAO INHIBITORS
Developed for the treatment of tuberculosis (iproniazid
derivatives) 1951
Not widely used today - small number of patients appear
to do better in MAOIs than TCAs or 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(1-3 weeks)
Selective MAOIs:
MAOIs:
Inhibitors of MAOMAO-A
Moclobemide, Clorgyline
Inhibitors of MAOMAO-B
Deprenyl, Selegiline
Hyperexcitation Syndrome
Interaction with drugs metabolized by MAOs (e.g.
Meperidine, SSRIs, TCAs, alcohol, CNS depressants )
- high fever, delirium and hypertension
SSRIs
Selective Serotonin Reuptake Inhibitors
Fluoxetine
Sertraline
Paroxetine
Citalopram
Fluvoxamine
(Labeled for obsessiveobsessive-compulsive disorder)
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
SSRIs
Mechanism - Specific serotonin uptake inhibitors
increase 55-HT by inhibiting reuptake
Fluoxetine is the prototype
Approximately 70% of depressed patients will respond to
an SSRI therapy at the end of 6 weeks
T1/2 of 16 24 hrs. except for fluoxetines metabolite
norfluoxetine (T1/2 = 8 days)
Fluoxetine and paroxetine inhibit liver enzymes,
particularly CYP450CYP450-2D6 DI with others eg. metoprolol
Drug-drug interactions
Drugdangerous with other antidepressants, MAOIs in particular
Serotonin Syndrome:
Syndrome:
hyperthermia, muscle rigidity, myoclonus, rapid changes in mental
status and vital signs.
- important to wait up to 6 weeks after medication is stopped, before
starting with another antidepressant
Heterocyclics
Second Generation heterocyclics
Amoxapine
Maprotiline
Trazodone
Bupropion
Heterocyclics
The second and third generation antidepressants are by
no means a homogeneous group they are sometimes
called ATYPICAL ANTIDEPRESSANTS
As with the TCA's , they all have variable bioavailability
High protein binding
Some have active metabolites
Trazodone and Venlafaxine have the shortest plasma halfhalflives, which mandates divided doses during the day
Heterocyclics
Amoxapine
NE reuptake inhibitor
DA receptor antagonism => parkinson's-like symptoms
Metabolite of Loxapine (an anti-psychotic) - retains some
antipsychotic activity
Useful if psychosis is present
Maprotiline
Blocks NE reuptake
Resembles desipramine with less sedative and
antimuscarinic side effects
Evokes seizures at high doses
Heterocyclics
Bupropion
Resembles amphetamine
Blocks DA / NE reuptake (NDRI) - minimal on 5HT
CNS stimulation
Inhibits appetite
Aggravates psychosis
Venlafaxine
Inhibit reuptake of 5HT , NE (SNRI)
No anticholinergic effects
Drowsiness, weakness
Short plasma half life
Heterocyclics
Trazodone
Blocks reuptake of serotonin
Highly sedative (hypnotic)
minimal antimuscarinic action
Nefazodone - less sedating
Mirtazapine
Derivative of Mianserin
Antagonizes 2-adrenergic receptors, thus increasing NE
and 55-HT release.
Very sedating
Weight gain and appetite stimulation
Uses of antidepressants
Depression:
Enuresis
Chronic pain
pain
neuropathic low dose TCA
nicotine dependence - Bupropion
ethanol withdrawal symptoms - Citalopram
Anti--Manic Drugs
Anti
Lithium (Li+) remains the drug of choice for the
treatment and prophylaxis of mania
Useful in refractory depression when added to
SSRIs or TCAs, but not a good antidepressant
alone..
alone
Acute manic episodes are managed with lithium
salts (carbonate or citrate) alone, or in
combination with:
1) carbamazepine
2) Valproic acid
Lithium
Li
Lithium - ADR
Has narrow therapeutic index needs periodic plasma
level monitoring 0.6 to 1.5 mEq/L
ADR:
GI upset
May decrease thyroid function
May induce ECG changes T wave inversion
Neuroleptics may produce more severe
extrapyramidal syndromes when combined with lithium
Not to be taken with thiazide diuretics - Lithium
clearance is reduced by 25%.