Antidepressants
CLINICAL FEATURES
• The principal symptoms of major depression are :
depressed mood and loss of pleasure or interest in all or nearly all of one’s usual activities and pastimes.
• insomnia (or sometimes hypersomnia); anorexia and weight loss (or sometimes hyperphagia and weight gain);
• Mental slowing and loss of concentration;
• feelings of guilt, worthlessness, and helplessness;
• thoughts of death and suicide; and overt suicidal
behavior.
Depression
For a diagnosis to be made,
• Symptoms must be present most of the day nearly every day for at least 2 weeks.
• it would appear that some people are more vulnerable than others.
• Factors that may contribute to vulnerability include genetic heritage, a difficult childhood, and chronic low self-esteem.
Depressive episodes are brought on by stressful life events, such as
bereavement, loss of a job, or childbirth.
Monoamine hypothsis
Depression can be treated with three major modalities :
) 1 pharmacotherapy ( ,
) 2 depression-specific psychotherapy (e.g ( .,
cognitive behavioral therapy or interpersonal psychotherapy
(,
) 3 somatic therapies, such as electroconvulsive therapy and (
transcranial magnetic stimulation .
For patients with mild to moderate depression, drug therapy and psychotherapy can be equally effective
.
For those with more severe depression, a combination of drug therapy and psychotherapy is better than either
intervention alone
.
BASIC CONSIDERATIONs
• All antidepressants appear equally effective.
• Differences relate primarily to side effects, drug interactions, and cost.
• Therapeutic responses to antidepressants develop slowly. Initial responses develop in 1 to 3 weeks.
Maximal responses may not be seen until 12 weeks.
• Antidepressant therapy should continue for 4 to 9
months after symptoms resolve.
BASIC CONSIDERATIONs
During treatment with antidepressants, especially initially, - the risk of suicide may increase
.
To reduce the risk of suicide, patients should be followed - closely by family members, caregivers, and the prescriber .
Suicide risk is greatest in children and young adults -
.
Selektif serotonin reuptake inhibitörleri
Fluoksetin ve paroksetin CYP2D6’yı güçlü şekilde inhibe ettikleri için TCA’lar, • antipsikotik ilaçlar ile bazı antiaritmik ilaçlar ve beta-blokerlerin eliminasyonunu engellerler .
Diğer CYP450 izozimleri de )2C9/19, 3A4, 1A2( SSRI’lerinden farklı düzeylerde • etkilenirler .
KC yetmezliği olan kişilerde doz azaltılmalıdır • .
The most common side effects of SSRIs
Fluoxetine and the other SSRIs do not block reuptake - of dopamine or norepinephrine (NE
(.
In contrast to the TCAs fluoxetine does not block - cholinergic, histaminergic, or alpha1-adrenergic
receptors
.
Compared with the TCAs and MAOIs, SSRIs are equally - effective, better tolerated, and much safer. Death by
overdose is extremely rare .
Most SSRIs have stimulant properties, and hence can - cause insomnia and agitation. This contrasts with TCAs,
which cause sedation .
Like most other antidepressants, SSRIs can cause weight -
. gain
Like all other antidepressants, SSRIs may increase the risk - of suicide
.
Sexual dysfunction (e.g., impotence, anorgasmia) is more -
common with SSRIs than with most other antidepressants
.
SSRIs can cause serotonin syndrome, especially when - combined with MAOIs. Symptoms include agitation,
confusion, hallucinations, hyperreflexia, tremor, excessive sweating and fever
.
Therefore, combined use of SSRIs and MAOIs is - contraindicated
Combined use with other serotonergic drugs should be - done with extreme caution
,
SNRIs block reuptake of serotonin and norepinephrine .
Pharmacologic effects are similar to those of the SSRIs, although the
SSRIs may be better tolerated .
The SNRIs are indicated
for major depression as well as
other disorders
The most common side effects of SNRIs include nausea, insomnia, and hypertension
.
SNRIs can also contribute to sexual dysfunction .
SNRIs, like SSRIs, can cause serotonin syndrome
.
Duloksetin :
is a potent inhibitor of CYP2D6, thereby increasing plasma levels of drugs (such as antipsicotics) metabolized by this
enzyme .
In addition to its use in depression, duloxetine is approved for fibromyalgia, generalized anxiety disorder, pain of
diabetic peripheral neuropathy, and chronic
musculoskeletal pain, including low back pain and pain from osteoarthritis
.
Tricyclic antidepressants (TCA)
TCAs block reuptake of NE and 5-HT and thereby intensify transmission at
noradrenergic and serotonergic synapses
.
The most common adverse effects of TCAs are sedation, orthostatic
hypotension, and anticholinergic effects (e.g., dry mouth, constipation (.
The most serious adverse effect of TCAs is cardiotoxicity, which can be lethal if an overdose is taken
.
TCAs can cause a hypertensive crisis if combined with an MAOI. Accordingly,
the combination is generally avoided .
TCAs intensify responses to direct-acting sympathomimetics (e.g., epinephrine)
and
diminish responses to indirect-acting sympathomimetics (e.g.,
amphetamine
(.
MAO Inhibitors
MAO is an enzyme found in the liver, the intestinal wall, and terminals of monoamine-containing
neurons .
The function of MAO in neurons is to convert monoamine neurotransmitters (NE, 5-HT, and
dopamine) into inactive products
.
MAO Inhibitors
In the liver and intestine, MAO serves to inactivate tyramine and other biogenic amines in food
.
The body has two forms of MAO, named MAO-A and MAO-B. In the brain, MAO-A inactivates NE and 5-HT ,
whereas MAO-B inactivates dopamine .
In the intestine and liver, MAO-A acts on dietary tyramine and other compounds
.
MAO Inhibitors
MAOIs increase neuronal stores of NE and 5 - HT, and thereby intensify transmission at noradrenergic and serotonergic synapses .
MAOIs are as effective as SSRIs and TCAs, but are potentially more
hazardous .
MAOIs are first-choice drugs only for patients with atypical depression .
All of the MAOIs used for depression are nonselective
.
That is, at therapeutic doses, they inhibit both MAO-A and MAO-B
.
One agent—selegiline (used for depression and Parkinson disease)—is selective for MAO-B at the low doses used for Parkinson disease, but is
nonselective at the higher doses used for depression
.
Like SSRIs and SNRIs (and unlike TCAs), MAOIs cause direct CNS stimulation
.
Like TCAs (and unlike SSRIs or SNRIs), MAOIs cause orthostatic hypotension
.
Patients taking MAOIs must not eat tyramine-rich foods
because hypertensive crisis can result .
Hypertensive crisis can be treated with an IV vasodilator (e.g., sodium nitroprusside, labetalol, phentolamine
(.
MAOIs must not be combined with indirect-acting sympathomimetics (e.g., amphetamine, cocaine)
because hypertensive crisis can result .
MAOIs must not be combined with SSRIs, SNRIs, or other serotonergic drugs because serotonin
syndrome could result
.
Atypical Antidepressants
Bupropion :
Bupropion is a unique antidepressant similar in structure to amphetamine
.
It has stimulant actions and suppresses appetite .
It’s mechanism may be related to blockade of dopamine and/or NE reuptake
.
Bupropion :
In addition to its use in depression, bupropion is approved as an aid to quit smoking
.
The most common adverse effects are agitation, headache, dry mouth, constipation, weight loss, GI
upset, dizziness, tremor, insomnia, blurred vision, and tachycardia
.
Mirtazapine :
Benefits appear to result from increased release of 5-HT and NE. The
mechanism is blockade of presynaptic alpha2-adrenergic receptors that serve to inhibit release
.
It is a powerful blocker of two serotonin receptor subtypes: 5-HT2 and 5-HT3. The contribution of this effect is unclear
.
Mirtazapin blocks histamine receptors and thus promotes sedation and
weight gain. Antidepressant effects equal those of SSRIs and may develop faster
.
Trazodon :
The drug is not very effective when used alone .
Because of its pronounced sedative effects, can be a helpful adjunct for patients with antidepressant-induced insomnia
.
Common side effects are sedation, orthostatic hypotension, and nausea
.
Trazodone can cause priapism )prolonged, painful erection (.
if trazodone is combined with a strong CYP3A4 inhibitor )e.g., ketoconazole, ritonavir(, dosage of trazodone should be reduced .
