Antidepressant drugs

Mood DisorderMood Disorder The most common mood disorders are:The most common mood disorders are:1.1. Major depression Major depression (unipolar depression).(unipolar depression).2.2. Manic-depressive illness Manic-depressive illness (bipolar disorder).(bipolar disorder).

Major depression and bipolar disorder are Major depression and bipolar disorder are pervasive mood altering illnesses pervasive mood altering illnesses affecting affecting energy, energy,

sleep, sleep, appetite, appetite, libido libido and the ability to function.and the ability to function.

IntroductionIntroduction The symptoms of The symptoms of depression aredepression are::1.1. Intense feelings of sadness.Intense feelings of sadness.2.2. Hopelessness. Hopelessness. 3.3. Despair.Despair.4.4. The inability to experience pleasure in The inability to experience pleasure in usual activities.usual activities. Mania Mania is characterized by is characterized by the opposite behaviorthe opposite behavior, that is:, that is: enthusiasmenthusiasm rapid thought and speech patternsrapid thought and speech patterns extreme self-confidence extreme self-confidence impaired judgment the brain.impaired judgment the brain...

Biogenic amine TheoryBiogenic amine Theory DepressionDepression is is due to a due to a deficiency of deficiency of

monoamines monoamines such as such as norepinephrine and norepinephrine and serotoninserotonin at certain key sites in the brain. at certain key sites in the brain.

ManiaMania is caused is caused by an over production by an over production of these neurotransmitters. of these neurotransmitters.

It is It is not known not known which of these neurochemical which of these neurochemical systems is most responsible for the systems is most responsible for the antidepressant activityantidepressant activity

All clinically useful antidepressant drugs potentiate, All clinically useful antidepressant drugs potentiate, either either directly or indirectlydirectly or indirectly, the actions of norepinephrine, , the actions of norepinephrine, dopamine, and/or serotonin in the brain. dopamine, and/or serotonin in the brain.

Antidepressant Drugs1.1. Tricyclic / polycyclic antidepressants Tricyclic / polycyclic antidepressants

(TCA).(TCA).2.2. Selective serotonin-reuptake inhibitors Selective serotonin-reuptake inhibitors

(SSRI). (SSRI). 3.3. Monoamine oxidase inhibitors (MAOI). Monoamine oxidase inhibitors (MAOI). Drugs used to treat mania:Drugs used to treat mania: Lithium salts. Lithium salts.

Tricyclic/polycyclic ntidepressantsTricyclic/polycyclic ntidepressants

older tricyclic antidepressantsolder tricyclic antidepressants1.1. ImipramineImipramine (the prototype).(the prototype).2.2. Amitriptyline Amitriptyline ..3.3. desipramine .desipramine .4.4. Nortriptyline (a demethylated derivative of imipramine).Nortriptyline (a demethylated derivative of imipramine).5.5. Protriptyline .Protriptyline .6.6. Doxepin.Doxepin.

7.7. Amoxapine.Amoxapine.8.8. Maprotiline Maprotiline second generationsecond generation

Tricyclics/PolycyclicsTricyclics/Polycyclics Examples: Examples: Amitriptyline, imipramineAmitriptyline, imipramine Mode of Action:Mode of Action:

Inhibit NE, 5-HT, DO re-uptakeInhibit NE, 5-HT, DO re-uptake Also have muscarinic and adrenergic effectsAlso have muscarinic and adrenergic effects

This is manifested in terms of side effectsThis is manifested in terms of side effects Clinical Effects: Clinical Effects: Elevate mood, mental alertness, reduces Elevate mood, mental alertness, reduces

morbid preoccupation in 50 – 70% of patientsmorbid preoccupation in 50 – 70% of patients

Mode of actionMode of action1.1. Inhibition of neurotransmitter uptake: Inhibition of neurotransmitter uptake: TCAs inhibit the TCAs inhibit the neuronal re-uptake of neuronal re-uptake of

norepinephrine, and serotonin into norepinephrine, and serotonin into presynaptic nerve terminals. presynaptic nerve terminals.

It has been suggested that It has been suggested that monoamine monoamine receptor densitiesreceptor densities in the brain may change in the brain may change over a 2 to 4 week period with drug use and over a 2 to 4 week period with drug use and may be important in the onset of activity. may be important in the onset of activity.

2. Blocking of receptors: 2. Blocking of receptors: TCAs block serotonergic, TCAs block serotonergic, αα1-adrenergic1-adrenergic, ,

histamine, and muscarinic receptors. histamine, and muscarinic receptors.

Mode of actionMode of action

ActionsActions TCAs TCAs elevate moodelevate mood, improve , improve mentalmental

alertness, increase physical activity, alertness, increase physical activity, and and reduce morbid reduce morbid preoccupation in preoccupation in 50 to 70% of individuals with major 50 to 70% of individuals with major depression. depression.

The The onset of the onset of the mood-elevation is mood-elevation is slowslow, requiring 2 weeks or longer., requiring 2 weeks or longer.

These drugs do not These drugs do not produce CNS produce CNS stimulation or mood elevation stimulation or mood elevation in in normal normal individuals. individuals.

ActionsActions Tolerance to the Tolerance to the anticholinergic anticholinergic

properties of the TCAsproperties of the TCAs develops develops within a within a short timeshort time. Some tolerance . Some tolerance to the autonomic effects of TCAs to the autonomic effects of TCAs develops.develops.

Physical and psychological Physical and psychological dependencedependence have been reported. have been reported.

The drugs can be used The drugs can be used for prolonged for prolonged treatment of depression without treatment of depression without loss loss of effectiveness.of effectiveness.

Therapeutic usesTherapeutic uses severe major depression. severe major depression. Some panic disorders. Some panic disorders. Imipramine Imipramine has been used to control has been used to control bed-bed-

wetting in childrenwetting in children (older than 6 years) by (older than 6 years) by causing contraction of the internal causing contraction of the internal sphincter of the bladder. sphincter of the bladder.

Note: At present it is Note: At present it is used cautiouslyused cautiously, because , because of the inducement of of the inducement of cardiac arrhythmias cardiac arrhythmias and other serious cardiovascular problems. and other serious cardiovascular problems.

Adverse effectsAdverse effects1.1. Antimuscarinic effectsAntimuscarinic effects2.2. CardiovascularCardiovascular3.3. Orthostatic hypotensionOrthostatic hypotension4.4. SedationSedation5.5. Precautions:Precautions: The tricyclic antidepressants should The tricyclic antidepressants should

be used with caution in be used with caution in manic-depressive patientsmanic-depressive patients. . 6. The tricyclic antidepressants have 6. The tricyclic antidepressants have a narrow a narrow therapeutic index;therapeutic index; for example, for example, 5 to 6 times the maximal daily dose 5 to 6 times the maximal daily dose of imipramine can be lethal. of imipramine can be lethal. Depressed patients Depressed patients who are suicidal should be given only limited who are suicidal should be given only limited quantities of these drugs and should be monitored quantities of these drugs and should be monitored closely. closely.

SELECTIVE SEROTONIN-SELECTIVE SEROTONIN-REUPTAKE INHIBITORS REUPTAKE INHIBITORS ((SSRI Inhibitors)SSRI Inhibitors) Examples:Examples:

Fluoxetine, Fluoxetine, Zoloft, PaxilZoloft, Paxil Mode of Action:Mode of Action:

Selectively block 5-HT reuptakeSelectively block 5-HT reuptake Clinical Effects:Clinical Effects:

1.1.Effective in treating depression, Effective in treating depression, 2.2.Obsessive –Compulsive Disorder Obsessive –Compulsive Disorder Fewer side effects than TCA’s. Fewer side effects than TCA’s.

((SSRI InhibitorsSSRI Inhibitors)) The SSRI are The SSRI are a new group a new group of chemically of chemically

antidepressant drugs that antidepressant drugs that specificallyspecifically inhibit serotonin reuptake.inhibit serotonin reuptake.

This contrasts with the tricyclic and block This contrasts with the tricyclic and block muscarinic, Hl-histaminic and muscarinic, Hl-histaminic and αα-adrenergic -adrenergic receptors. receptors.

Compared with tricyclic antidepressants, Compared with tricyclic antidepressants, the SSRIs cause fewer anticholinergic the SSRIs cause fewer anticholinergic effects and lower cardiotoxicity. effects and lower cardiotoxicity.

FluoxetineFluoxetine It is the prototype of SSRI. It is the prototype of SSRI. Fluoxetine is as effective in the treatment of Fluoxetine is as effective in the treatment of major major

depression depression as tricyclic antidepressants. as tricyclic antidepressants. The drug is The drug is free of most of the troubling side free of most of the troubling side

effects of tricyclic antidepressants, including effects of tricyclic antidepressants, including anti- anti- cholinergic effects, orthostatic hypotension, and cholinergic effects, orthostatic hypotension, and weight gain.weight gain.

Fluoxetine is preferred over tricyclic Fluoxetine is preferred over tricyclic antidepressantsantidepressants

Therapeutic usesTherapeutic uses In depression, where it is as effective as the In depression, where it is as effective as the

tricyclic antidepressants. tricyclic antidepressants.

Fluoxetine is effective in treating obsessive-Fluoxetine is effective in treating obsessive-compulsive disorder.compulsive disorder.

The drug has been used for a variety of The drug has been used for a variety of other indications, including other indications, including anorexia anorexia nervosa, panic disorder, pain associated nervosa, panic disorder, pain associated with diabetic neuropathy, and for pre- with diabetic neuropathy, and for pre- menstrual syndrome.menstrual syndrome.

Adverse affectsAdverse affects:: Gastrointestinal symptoms.Gastrointestinal symptoms. Sleep disturbance (insomnia and somnolence ) Sleep disturbance (insomnia and somnolence ) sexual dysfunction,sexual dysfunction, anxiety (acutely), insomnia, tremor. anxiety (acutely), insomnia, tremor. Overdoses of fluoxetine do Overdoses of fluoxetine do not not cause cause cardiac cardiac

arrhythmias but can cause seizures. For example, in a arrhythmias but can cause seizures. For example, in a report of patients who took an report of patients who took an overdose of fluoxetine overdose of fluoxetine (up to (up to 1200 mg 1200 mg compared with 20 mg/day as a compared with 20 mg/day as a therapeutic dose) about half of the patients had no therapeutic dose) about half of the patients had no symptoms.symptoms.

MAO InhibitorsMAO Inhibitors Examples: Examples: Phenylzine, Phenylzine,

isocarboxazideisocarboxazide Mode of Action ofMode of Action of MAO enzyme MAO enzyme : :

MAO MAO inactivates excess inactivates excess NE, DO, 5-NE, DO, 5-HTHT

Inhibitors increase the amounts of these Inhibitors increase the amounts of these neurotranmittersneurotranmitters

Physiological Effects:Physiological Effects:Depression Depression

MONOAMINE OXIDASE MONOAMINE OXIDASE INHIBITORSINHIBITORS

((MAO) is a MAO) is a mitochondrial enzyme mitochondrial enzyme found in neural and found in neural and other tissues, such as other tissues, such as the gut and liver.the gut and liver.

MONOAMINE OXIDASE MONOAMINE OXIDASE INHIBITORSINHIBITORS

The MAO inhibitors The MAO inhibitors may may irreversibly irreversibly or reversibly inactivate the enzyme,or reversibly inactivate the enzyme, permitting neurotransmitter molecules to permitting neurotransmitter molecules to escape degradationescape degradation and therefore to both and therefore to both accumulate within the accumulate within the presynapticpresynaptic neuron neuron and to leak into the and to leak into the synaptic space. synaptic space.

This causes This causes activation of activation of norepinephrine and serotonin norepinephrine and serotonin receptors, receptors, and may be responsible for and may be responsible for the antidepressant action of these drugs. the antidepressant action of these drugs.

MONOAMINE OXIDASE MONOAMINE OXIDASE INHIBITORSINHIBITORS

1.1. Phenelzine.Phenelzine.2.2. Isocarboxazid.Isocarboxazid.3.3. tranylcypromine,.tranylcypromine,. Use of MAO inhibitors is now Use of MAO inhibitors is now

limited because of the limited because of the complicated dietary restrictions complicated dietary restrictions required of patients taking MAO required of patients taking MAO inhibitors.inhibitors.

Receptor

MAO

IncreasedNT

Mechanisms of Action of MAOIMechanisms of Action of MAOI

Dopamine5-HT

NEMAOI

-Dopa

Mode of actionMode of action MAOI form stable complexes with the MAOI form stable complexes with the

enzyme(MAO), causing irreversible enzyme(MAO), causing irreversible inactivation.inactivation.

This results in increased This results in increased stores of stores of norepinephrine, serotonin and dopamine norepinephrine, serotonin and dopamine within the neuronwithin the neuron, and subsequent , and subsequent diffusion diffusion of of excess neurotransmitter into the excess neurotransmitter into the synaptic synaptic space.space.

These drugs These drugs inhibit not only MAO in brain, inhibit not only MAO in brain, but but oxidasesoxidases that catalyze that catalyze oxidative deamination oxidative deamination of drugs and potentially toxic substances, of drugs and potentially toxic substances, such such as tyramine, which is found in certain foods. as tyramine, which is found in certain foods.

The MAO inhibitors therefore show a The MAO inhibitors therefore show a high high incidence of drug-drug and drug- food incidence of drug-drug and drug- food interactionsinteractions..

Therapeutic usesTherapeutic uses1.1. Depressed patients who are unresponsive or Depressed patients who are unresponsive or

allergic allergic to tricyclic antidepressants or who to tricyclic antidepressants or who experience strong anxiety. experience strong anxiety.

2.2. Patients with Patients with low psychomotor activity low psychomotor activity may may benefit from the stimulant properties of MAO benefit from the stimulant properties of MAO inhibitors. inhibitors.

3.3. Treatment of Treatment of phobic states. phobic states. 4.4. Atypical depressionAtypical depression, may respond to MAOIs. , may respond to MAOIs.

Atypical depression is characterized by labile Atypical depression is characterized by labile mood, rejection sensitivity and appetite mood, rejection sensitivity and appetite disorders. disorders.

Adverse effectsAdverse effects Tyramine,Tyramine, contained in certain foods, such contained in certain foods, such

as aged cheeses, chicken liver, beer, and red as aged cheeses, chicken liver, beer, and red wineswines, is , is normally inactivated by MAO in normally inactivated by MAO in the gut. the gut.

Individuals receiving a Individuals receiving a MAO inhibitor MAO inhibitor are are unable to unable to degrade tyramine obtained degrade tyramine obtained from from the diet.the diet.

Tyramine causes the release of Tyramine causes the release of large large amounts of stored catecholamines from amounts of stored catecholamines from nerve terminals, nerve terminals, resulting in headache, resulting in headache, tachycardia, nausea, hypertension, cardiac tachycardia, nausea, hypertension, cardiac arrhythmias, and stroke. arrhythmias, and stroke.

Lithium SaltsLithium Salts Mode of Action:Mode of Action:

AffectsAffects inositol triphosphate inositol triphosphate (IP3), blocks Na(IP3), blocks Na++ channels channels

Clinical Effects:Clinical Effects:Treatment of manic/depressive Treatment of manic/depressive patientspatients

VERY TOXICVERY TOXIC

Lithium saltsLithium saltsClinical usesClinical uses1.1.Used prophylactically in Used prophylactically in

treating manic-depressive treating manic-depressive patients .patients .

2.2.Treatment of Treatment of manic episodesmanic episodes. . 3.3.Effective in treating 60 to Effective in treating 60 to

80% of patients exhibiting 80% of patients exhibiting mania and hypomania. mania and hypomania.

Lithium saltsLithium salts

Mechanism of actionMechanism of action Although many cellular processes are Although many cellular processes are

altered by treatment with lithium altered by treatment with lithium salts, salts, the mode of action is unknown.the mode of action is unknown.

It is currently proposed that Lithium It is currently proposed that Lithium acts by acts by altering the cellular altering the cellular concentration of the second concentration of the second messenger, inositol triphosphate messenger, inositol triphosphate (IP3)(IP3)

Lithium saltsLithium saltsPharmacokineticPharmacokinetic1.1. Lithium is given orally.Lithium is given orally.2.2. The ion is excreted by the kidney. The ion is excreted by the kidney. 3.3. Lithium salts are very toxic. Lithium salts are very toxic. 4.4. Their safety factor and Their safety factor and

therapeutic index are extremely therapeutic index are extremely low-low--comparable to those of -comparable to those of digitalis. digitalis.

Lithium saltsLithium saltsAdverse effects:Adverse effects:1.1. Ataxia.Ataxia.2.2. Tremors.Tremors.3.3. Confusion.Confusion.4.4. Convulsions. Convulsions. Lithium causes no noticeable effect on Lithium causes no noticeable effect on

normal individuals. normal individuals. It is not a sedative, euphoriant or It is not a sedative, euphoriant or

depressant. depressant.