ANTIDEPRESSANTS

OVERVIEW OF DEPRESSION

DepressionDepression is a state of low mood and aversion to activity. Depression is a syndrome.

Depressive syndromes :Depressive syndromes :- major depression(with subtypes)- dysthymic disorder(low-grade but

very chronic form of depression, which lasts for more than 2 years)

- minor depression

CLINICAL PRESENTATION(SYMPTOMS) Emotions :Emotions : depressed mood loss of interest or pleasure in most or all activities

Ideation Ideation thoughts of worthlessness or guilt recurrent thoughts about death or suicide

Somatic symptoms Somatic symptoms change in appetite or weight low energy psychomotor retardation or agitation poor concentration

SOME DEPRESSION FEATURES

Depression is an illness, not a is an illness, not a choicechoice, and is just as socially debilitating as coronary artery disease and more debilitating than diabetes mellitus or arthritis.

Up to 15% of severely depressed patients will ultimately commit suicide.

Depression can be successfully successfully treatedtreated.

DepressionDepression is episodic, with untreated episodes commonly lasting 6 to 24 months, followed by recovery or remission.

BIOCHEMICAL BASIS OF DEPRESSION

NoradrenergiNoradrenergic c synapse synapse structurestructure

SIMPLE PICTURE

BIOCHEMICAL BASIS OF DEPRESSION Monoamine Hypothesis: Monoamine Hypothesis: depression was due to a deficiency of monoamine neurotransmitters, notably nor-epinephrine (NE) and serotonin (5-hydroxytryptamine [5HT])

EVIDENCE FOR MONOAMINE HYPOTHESIS Certain drugs that depleted these neurotransmitters could

induce depression

Known antidepressants at that time both had pharmacological actions that boosted these neurotransmitters.

The idea was that the "normal" amount of monoamine neurotransmitters became somehow depleted, perhaps by an unknown disease process, by stress, or by drugs leading to the symptoms of depression.

An overly simplified notion about depression

BIOCHEMICAL BASIS OF DEPRESSION

Neurotransmitter Receptor Neurotransmitter Receptor Hypothesis Hypothesis

The neurotransmitter receptor theory posits that something is wrong with the receptors for the key monoamine neurotransmitters.

In this figure, monoamine In this figure, monoamine neurotransmitter is depleted (see red neurotransmitter is depleted (see red circle).circle).

The consequences of monoamine neurotransmitter depletion could cause the postsynaptic receptors to abnormally up-regulate (indicated in red circle). This up-regulation or other receptor dysfunction is hypothetically linked to the cause of depression.

there is no clear and convincing evidence that monoamine deficiency accounts for depression

there is no clear and convincing evidence that excesses or deficiencies of monoamine receptors account for depression;

there is growing evidence that despite apparently normal levels there is growing evidence that despite apparently normal levels of monoamines and their receptors, these systems do not of monoamines and their receptors, these systems do not respond normallyrespond normally

MONOAMINE HYPOTHESIS OF GENE EXPRESSIONThe monoamine hypothesis of gene expression proposes that depression itself is linked to abnormal functioning of neurotransmitter-inducible gene expression, particularly neurotrophic factors such as brain-derived neurotrophic factor (BDNF), leading to atrophy and apoptosis of critical hippocampal neurons.

MECHANISM OF ACTION

All antidepressants have a common action on monoamine neurotransmitters: they increase monoamine neurotransmission,

leading to changes in gene expression in the neurons targeted by the monoamines. This includes desensitization of neurotransmitter receptors, leading to both therapeutic action and tolerance to side effects.

Effect develops only after 10-14 days.

ANTIDEPRESSANTS TYPES

1 Selective serotonin reuptake inhibitors (SSRIs) Citalopram, Escitalopram, Fluoxetine

2 Serotonin-norepinephrine reuptake inhibitors (SNRIs) Duloxetine, Venlafaxine

3 Norepinephrine reuptake inhibitors (NRIs)

Atomoxetine, Reboxetine

4 Norepinephrine-dopamine reuptake inhibitors (NDRIs) Bupropion, Methylphenidate

5 Tricyclic antidepressant (TCAs) Amitriptyline, Clomipramine, Imipramine

6 Tetracyclic antidepressants (TeCAs) Mianserin, Maprotiline

7 Monoamine oxidase inhibitors (MAOIs) – reversible and irreversible Phenelzine, Selegiline(MAO-B),Moclobemide, Tranylcypromine

TRICYCLIC ANTIDEPRESSANTS(TCA)

- Their organic chemical structure contains three rings.

- The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs).

As other tricyclic drugs (antipsychotic) they have antimuscarinic, antihistaminic and alfa-receptor blocking activity.

TCA SIDE EFFECTS

Drowsiness

Dry mouth

Blurred vision

Constipation

Urinary retention

Dizziness

Impaired sexual functioning

Increased heart rateDisorientation or

confusionHeadacheLow blood pressureSensitivity to

sunlightIncreased appetiteWeight gain

Toxocity: 3 C’s – coma, convulsions, cardiootoxicity.

MAO INHIBITORS

Reversible or irreversible inhibition of monoaminooxydase.

Monoamine oxidase exists in two subtypes, A and B.

Both forms are inhibited by the original MAO inhibitors, which are therefore nonselective

The A form metabolizes the neurotransmitter monoamines most closely linked to depression

MAO A inhibition is linked both to antidepressant action and to the troublesome hypertensive side effects of the MAO inhibitors.

MAO INHIBITORS CON’T

Nowadays we have selective inhibitors of MAO A or of MAO B and reversible inhibitors.

Reversible inhibitors of MAO A called RIMAs.

Exogenous amines(tyramine in cheese) can markedly elevate blood pressure in the presence of irreversible MAO inhibitors.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS(SSRI)Inhibition of serotonin reuptake into the presynaptic cell,

increasing the level of serotonin available to bind to the postsynaptic receptor

SSRIS PHARMACOLOGY

Uses:

- Major depresion

- Bulimia

- Anxiety disorders

- Premenstrual dysphoric disorder

Side effects:

- Anxiety

- Bruxism(the habit of grinding the teeth)

- Agitation

- Weight loss

- Sexual dysfunction(delay ejaculation)

1 2

3 4

Cytochrome P450 – CYP450

CNS STIMULANTS

CNS STIMULANTS

Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both.

Common effects:Increased alertness, awareness, wakefulness, endurance, productivity, and motivation, increased arousal, locomotion, heart rate, and blood pressure, and the perception of a diminished requirement for food and sleep.

Stimulants are widely used throughout the world(social drugs, OTC drugs, illegal drugs).

CAFFEINE discovered by a German

chemist in 1819 xanthine alkaloid Source : beans, leaves, and

fruit of some plants, where it acts as a natural pesticide kills certain insects feeding on the plants

coffee plant, leaves of the tea, kola nut, guarana berries

PHARMACOLOGY

Half-life—varies widely among individuals according to age, liver function, pregnancy, some concurrent medications, and velocity of

metabolism - approximately 4.9 hoursIn women taking oral contraceptives 5–10 hoursIn pregnant women - 9–11 hoursSevere liver disease - up to 96 hoursSmoking can shorten caffeine's half-life

Caffeine is metabolized in the liver by the cytochrome P450 1A2 into:- Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma.

CNS EFFECTS

increased alertness and wakefulness,

faster and clearer flow of thought

increased focus and better general body coordination

readily crosses the blood–brain barrier

caffeine molecule is structurally similar to adenosine

binds to adenosine receptors on the surface of cells without activating them

caffeine acts as a competitive inhibitor

competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA

Mechanism of actionMechanism of action

AMPHETAMINE GROUPAmphetamine

Methamphetamine

Levoamphetamine

Dextroamphetamine

Major neurobiological mechanisms:-most widely studied neurotransmitter with regard to amphetamine action is dopamine-increasing dopamine release from pre-synaptic membrane-amphetamine inhibit dopamine reuptake

PHYSICAL EFFECTS

Reduced appetite

Increased/distorted sensations,

Hyperactivity

Dilated pupils

Restlessness

Tachycardia

Increased blood pressure

Sweating

Uncontrollable movements or shaking

PSYCHOLOGICAL EFFECTS

Euphoria (via increased dopamine) Increased anxiety (via increased

norepinephrine) alertness concentration energy self-esteem self-confidence aggression

Also:-Dependence-Tolerance-Withdrawal syndrome

MODAFINIL

treatment of narcolepsy, shift work sleep disorder and excessive daytime sleepiness associated with obstructive sleep apnea

increase the levels of various monoamines dopamine, noradrenaline and serotonin in synaptic cleft

activates glutamatergic circuits while inhibiting GABAergic neurotransmission

SIDE EFFECTS

The most common side effects of modafinil in clinical trials are:

headache

upper respiratory tract infection

Nausea

Nervousness

Anxiety

insomnia