ANTIDEPRESSANT AGENTS
Mood disorders (also known as affective disorders) are syndromes consisting of signs
and symptoms that are clearly abnormal for the individual experiencing them.
No single physiologic mechanism for mood disorders has been identified.
Nonetheless, considerable evidence suggests the involvement of:
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several neurotransmitter systems, especially the monoamines (noradrenergic,
serotoninergic, and perhaps dopaminergic pathways)
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abnormalities in the hypothalamic-pituitary-adrenal (HPA) and
hypothalamic-pituitary-thyroid (HPT) axes.
Chronic hyperactivity of the HPA axis is arguably the biologic finding that is most often
reported in severe and psychotic depression, and it normalizes with clinical recovery.
Several measures of HPA-axis hyperactivity have been reported in depressed patients.
These include:
• increased concentrations of CRF in CSF,
• a blunted ACTH response to exogenous CRF administration,
• decreased CRF receptor density in the frontal cortex of suicide victims,
• pituitary and adrenal gland enlargement,
• increased ACTH and cortisol production,
• nonsuppression of plasma cortisol levels after the administration of
dexamethasone (the dexamethasone suppression test).
It has been posited that mood disorders are caused by relative deficiencies in the
availability of the norepinephrine (NE) or the serotonin (5-hydroxytryptamine [5-HT])
within the central nervous system, perhaps involving alterations in receptor function,
signal transduction, or both.
A multitude of alterations in the activity of the HPT axis have been observed in patients
with depression.
Such abnormalities include:
• increased TRH concentrations in CSF,
• blunted or exaggerated TSH response to TRH stimulation, decreased nocturnal
plasma TSH concentrations,
• the presence of antimicrosomal thyroid or antithyroglobulin antibodies.
Tricyclic antidepressants (TCAs )
TCAs act at several transporters and receptors, but their antidepressant effect is likely
produced by the blocking of the reuptake of NE, 5-HT, or both at their presynaptic
terminals, increasing the availability of these neurotransmitters.
The TCAs can be subdivided into the tertiary amines, which are dual 5-HT/NE reuptake
inhibitors (e.g., amitriptyline, imipramine, clomipramine) and the secondary amines,
which are primarily NE reuptake inhibitors (e.g., desipramine, nortriptyline).
The use of TCAs is limited by their unfavorable side-effect profile (largely resulting
from their anticholinergic, antiadrenergic, and antihistaminic properties); these side
effects include:
• blurred vision, dry mouth, tachycardia, constipation, urinary retention, cognitive
dysfunction, postural hypotension, dizziness, sedation, weight gain, and sexual
dysfunction.
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TCAs also have a narrow therapeutic index and are lethal in overdose (resulting in part
from an inhibition of sodium channels that causes a slowing of cardiac conduction and
potentially fatal arrhythmias).
Clinical indications: major depression, especially in patients with psychomotor
retardation, sleep disturbances, poor appetite and weight loss; bipolar affective
disorders, acute panic attacks, phobic disorders, chronic pain states.
Selective Serotonine Reuptake Inhibitors (SSRI)
fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram.
These agents all share the property of blocking the reuptake of 5-HT, but there is
increasing evidence that they produce other effects as well.
The SSRIs are effective in treating depression and many primary anxiety disorders.
Perhaps most importantly, these medications are safe in overdose.
The SSRIs have a relatively mild side-effect burden.
Sexual side effects of these medications (i.e., delayed ejaculation, anorgasmia, decreased
libido) are being increasingly recognized and studied and are one of the leading causes
of discontinuance or noncompliance.
Interactions: with MAOI- „serotonin syndrome”
Newer agents are believed to act on serotoninergic and noradrenergic pathways in the
brain by a variety of mechanisms, including dual 5-HT/NE reuptake blockade
(venlafaxine), 5-HT2 blockade (trazodone, nefazodone, mirtazapine), and alpha2
autoreceptor blockade (mirtazapine).
Venlafaxine
Pharmacological effects:
- sympathomimetic effects
- antidepressant effect
Indications:
- major depression
- neuropathic pain
Side effects:
- hypertension
- headache, anxiety, insomnia, agitation
Interactions:
-inhibition of metabolism of haloperidol
Mirtazapine
Pharmacological effects:
- antidepressant effect
- sedation
- hypnotic and anxiety-relieving actions
Indications:
- major depression
- depression with anxiety, agitation and sleep disturbances
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Side effects:
- weight gain
- sedation and autonomic effects
Trazodone and nefazodone
Pharmacological effects:
- antidepressant effect
- sedation
- antimuscarinic effects (nefazodone)
Indications:
- major depression
- depression with anxiety, agitation and sleep disturbances
Side effects:
- sedation and autonomic effects, rarely hepatotoxicity
- suicide risk in children and adolescents
Interactions:
- inhibition of metabolism of alprazolam and triazolam
Bupropion was originally thought to act as a dopamine and NE reuptake inhibitor, but
its mechanism of action remains somewhat obscure.
In addition to having FDA approval for depression, bupropion is approved for smoking
cessation (partial agonist nACh-receptor).
Bupropion
Pharmacologic effects:
- antidepressant effect
- stimulation of CNS
Indications:
- major depression
- nicotine dependence
Side effects:
- anxiety, agitation, dizziness, dry mouth,
- aggravation of psychosis,
- at high doses- seizures
CLASSICAL (non-selective) MAO-INHIB
PHENELZINE
TRANYLCYPROMINE
They are rarely used because their use is complicated by side effects (including
hypotension), lethality in overdose, and lack of simplicity in dosing.
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Patients treated with MAOIs must follow a specific tyramine-free diet because of
the potential for a pharmacodynamic interaction with tyramine that can result in
a hypertensive crisis.
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Drugs that have been reported to interact with MAOIs include carbamazepine,
cyclobenzaprine, dextromethorphan, fenfluramine, certain hypoglycemics, Ltryptophan, meperidine, selective serotonin reuptake inhibitors (SSRIs),
stimulants, sympathomimetics, and TCAs.
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Nonetheless, the MAOIs appear to be more effective than other antidepressants
in the treatment of atypical depression, though their use is usually limited to
psychiatrists who have experience with these agents.
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MAOIs are also often effective in patients with depression that is refractory to
treatment with other antidepressants.
Reversible inhibitors of monoamine oxidase A
MOCLOBEMIDE
If tyramine is absorbed from the gut, MAO-B is able to degrade it and the food reaction
seen with classical MAOIs is very unlikely to occur.
Also since the action of moclobemide on MAO-A is reversible, high concentrations of
tyramine will displace the drug from the enzyme, further facilitating tyramine
degradation.
If moclobemide is taken after meals, then inhibition of MOA-A in the gut during
absorption of tyramine will be minimised, providing further protection.
Enzyme inhibition by moclobemide lasts than 24 h after a single dose.
MOCLOBEMIDE
Pharmacokinetics
– Oral absorption is good but there is substantial first-pass
metabolism, partially to an active metabolite.
– Extensive hepatic metabolism gives a short half-life.
Unwanted effects
– Unwanted effects are:
CNC stimulation can produce sleep disturbance or agitation
nausea
dizziness, headache.
Drug interactions
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Inhibition of cytochrome P450 activity in the liver by
cimetidine substantially reduces the metabolism of
moclobemide and smaller starting doses are recommended
in this situation.
BIPOLAR DISORDER
Bipolar disorders include:
bipolar I disorder (involving the presence of one or more manic or mixed episodes, often
alternating with major depressive episodes),
bipolar II disorder (recurrent major depressive episodes with hypomanic episodes),
cyclothymic disorder .
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Cyclothymic disorder consists of at least 2 years of fluctuating mood disturbance
involving numerous periods of hypomanic symptoms and numerous periods of
depressive symptoms.
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Sleep deprivation or antidepressants can induce a manic episode in persons with
bipolar disorder but not in persons without bipolar disorder; these may be the
first manic episodes in a case of hitherto undiagnosed bipolar disorder.
Stressful life events, changes in sleep-wake cycles, and substance abuse may
affect the course of illness and lengthen time to recovery.
A mixed episode is a period of at least 1 week during which the patient meets the
criteria for having a major depressive episode and a manic episode
simultaneously.
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As with both major depressive episodes and manic episodes, a mixed episode is a
mood disturbance sufficiently severe to cause marked impairment in functioning
(such as necessitating hospitalization to prevent harm to self or others or having
associated psychotic features).
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Patients in the mixed state are dysphoric but hyperactive, agitated, and unable to
sleep.
A hypomanic episode, which is less severe than mania, is a distinct period of
elevated, expansive, or irritable mood lasting at least 4 days, during which time
three or more symptoms of a manic episode are experienced (four if the mood is
only irritable).
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The symptoms represent an unequivocal change in functioning and are
observable by others but are not severe enough to cause marked impairment or
to necessitate hospitalization.
No psychotic features are present.
Thus, a hypomanic episode can be thought of as a mild manic episode.
Research indicates that 5% to 15% of persons with hypomania will ultimately
develop a manic episode.
Lithium
• It is now considered the gold standard for treatment of bipolar disorder.
• Remarkably, the mechanism of action of lithium remains unknown, though some
evidence suggests that it acts via signal transduction pathways such as the
phosphatidylinositol second messenger system.
• As with other mood stabilizers, full improvement with lithium may take several
weeks.
• Lithium is most effective in classic bipolar disorder, which consists of discrete
episodes of mania and depression, with symptom-free periods between episodes.
• Continued medication use reduces the number and intensity of episodes of illness.
• Renal and thyroid function should be assessed before initiating treatment with
lithium, and an electrocardiogram should be obtained.
• Lithium is a natural element and is distributed with the total body water. It is
excreted unchanged into the urine.
• Diuretic therapy, sodium restriction, and sodium wasting increase reabsorption
of lithium and thus increase serum levels.
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Patients taking lithium should therefore avoid nonsteroidal anti-inflammatory
drugs and diuretics, and they should maintain uniform salt intake.
Administering lithium with meals may minimize gastrointestinal side effects.
Serum levels of lithium must be monitored.
The goal for the treatment of acute mania is a lithium level of 1.0 to 1.2 mEq/L.
Serum levels should be measured 10 to 12 hours after the last oral dose, and
levels should not be drawn sooner than 4 to 5 days after the latest change in
dosage.
Lithium levels should be monitored periodically, and renal function indicators
(i.e., blood urea nitrogen and serum creatinine) and TSH should be measured
every 6 months.
Common side effects include:
cognitive slowing, nausea, diarrhea, polyuria, polydipsia, weight gain, tremor,
and a metallic taste in the mouth.
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Several anticonvulsant medications are also effective as mood stabilizers,
including valproic acid/divalproex sodium and carbamazepine.
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These agents may act by decreasing neuronal membrane excitability, perhaps by
effects on -aminobutyric acid (GABA) systems.
Carbamazepine (Tegretol)
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It is now considered to be a primary drug for the treatment of partial and tonicclonic seizures (detalis will be discussed during lecture ”Antiepileptics”) .
• It is closely related (tricyclic structure) to imipramine and other classical
antidepresants and is effective in treatment of bipolar depression.
• It is also primary agent for treatment of trigeminal neuralgias.
Mechanism of action of carbamazepine:
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Blocks sodium channels at therapeutic concentration and inhibits high-frequency
repetitive firing in neurons (antiepileptic activity)
• Possible mechanisms involved in bipolar disorder treatment:
• Carbamazepine inhibits uptake and release of norepinephrine from brain
synaptsomes - antidepressive mechanism of action
• Antimanic activity – inhibition of DA receptor super sensitivity development
• Recent evidence suggests that the action of GABA can be potentiated by
carbamazepine. – increasing of GABA-B receptor density and inhibition of GLU
activity
Most common dose-related adverse effects are:
• diplopia and ataxia
• mild GI irritation
• unsteadiness
Other complications:
• hyponatremia and decreased of osmolality
• hypersensitivity reactions (dermatitis, eosinophilia)
• impotence
Valproic acid and Sodium valproate (Depakine)
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Valproic acid/divalproex sodium appears to be more effective for manias that are
dysphoric or mixed and for rapid cycling.
Mechanism of action of valproate:
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At therapeutically relevant concentrations, valproate inhibits sustained repetitive
firing induced by depolarization of neurons and appears to be mediated be a
prolonged recovery of voltage-activated NA+ channels from inactivation
(similarity to carbamazepine).
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Also reducing low-threshold (T) Ca2+ currents .
Another potential mechanism: increasing of GABA (effects in vitro):
valproate can stimulate the activity of the GABA synthetic enzyme, glutamic acid
decarboxylase (GAD) and
inhibit GABA degenerative enzymes, GABA transaminase and succinic
semialdehyde dehydrogenase leading to increase of GABA
Most common dose-related adverse effects are:
 anorexia, nausea, vomiting, abdominal pain, heartburn
 sedation, ataxia, tremor (the drug should gradually to
avoid these symptoms)
 transient alopecia
Other complications:
 hepatotoxicity (elevation of AST is observed in up to 40% patients primary adverse reaction ), children below 2 years of age were
especially likely to suffer fatal hepatic injury; most fatalities have
occurred within 4 months after initiation of therapy.
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Lamotrigine (Lamictal)
• Lamotrigine has been shown to be effective in the acute treatment of bipolar
depression and maintenance therapy of bipolar disorder, but it does not appear
to possess acute antimanic properties.
Mechanism of action
• Lamotrigine blocks sustained repetitive firing induced by depolarization of
neurons, an action consistent with blockage of voltage-dependent Na+ channels.
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The mechanism is similar to those observed with carbamazepine, however
antimaniac activity is still unknown.
Lamotrigine toxicity
 dizziness, headache, ataxia, blurred or double
 nausea, vomiting
 severe rash (hypersensitivity reaction) - risk may be diminished by
slow and low dose administration
 few cases of Stevens-Johnson syndrome
Atypical antipsychotic medications, including:
• clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), quetiapine
(Seroquel), and ziprasidone (Geodon), are being studied as possible treatments
for bipolar disorder.
• Evidence suggests clozapine may be helpful as a mood stabilizer for people who
do not respond to lithium or anticonvulsants.
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Other research has supported the efficacy of olanzapine for acute mania, an
indication that has recently received FDA approval.
Olanzapine may also help relieve psychotic depression.
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