pharmacologyofantidepressa.ppt

“Pharmacology of antidepressants”Objectives

1. Know the different classes of antidepressant

4. Know the factors that influence the choice of antidepressant

2. Know the main subtypes of depressive disorder

3. Know the diagnostic criteria for depression

5. Know the basics of depression etiology

“Pharmacology of antidepressants”Objectives

9. Know the neurotrophic hypothesis of depression and antidepressant action

6. Know the neuroanatomical features of depression

7 . Know the mechanisms of antidepressant drug action

8. Know the monoamine depletion hypothesis of depression

“Pharmacology of antidepressants”Overview

Classification of antidepressant drugs

What is depression?

Factors affecting drug choice

Mechanisms of antidepressant drug action

Neuroanatomy of depression

Hypotheses of depression

Currently available antidepressants

Tricyclics

Amitriptyline (Elavil)

Desipramine (Norpramin)

Imipramine (Tofranil)

Nortriptyline (Pamelor)


Monoamine oxidase inhibitors (MAOI)

Phenelzine (Nardil)

Tranylcypromine (Parnate)

Moclobemide (Manerix)


Selective serotonin reuptake inhibitors (SSRI)

Citalopram (Celexa)

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

Fluvoxamine (Luvox)


Triazolopyridines Nefazodone (Serzone), Trazodone (Desyrel)

Aminoketone - Bupropion (Wellbutrin)

5-HT/NE reuptake inhibitor - Venlafaxine (Effexor)

Tetracyclic - Mirtazapine (Remeron)

Other antidepressants

What is depression?

Diagnostic criteria

Neurochemical features

Neuroanatomical features

Subtypes of depression

Etiology (causes)

Major depression

Dysthymic disorder

Melancholic depression


Atypical depression

Others, e.g. bipolar disorder (Dr. Filtz)

Features of melancholic depression


Episodic

Anhedonia (unable to cheer up)

Anorexia, weight loss

Insomnia

Worse in the morning

Tendency to respond preferentially to electroconvulsive therapy (ECT), TCAs and SSRIs

Features of atypical depression


Chronic (not episodic)

Can cheer up temporarily

Overeating, weight gain

Hypersomnia (sleep more)

Worse in the evening

Tendency to respond preferentially to MAOIs

Dysthymic disorder


Persistent depression

Milder than major depression

Risk of developing into major depression

Responsive to a variety of antidepressants


Main point:There are different subtypes of depressive disorder.

The relative efficacy of different types of antidepressant can depend to an extent on the subtype of depression being treated

Diagnostic criteria for depression1. Depressed mood most of the time

2. Markedly diminished pleasure in almost all activities

3. Significant weight loss or gain, or change in appetite

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day

6. Fatigue or loss of energy nearly every day

7. Feelings of worthlessness or guilt nearly every day

8. Diminished ability to concentrate or make decisions

9. Recurrent thoughts of death or suicide

Diagnostic criteria for depression

Major depressive episode (melancholic or atypical)At least five symptoms, including #1 and/or #2

Dysthymic disorder

At least three symptoms, including #1

Diagnostic criteria for depression

Main point:The diagnosis of depression relies on interpretation of behavioral and subjective characteristics of the patient

No lab tests available

Antidepressants – drug choice


In general, antidepressants are equal in efficacy when administered in comparable doses

Efficacy

Individually, patients may respond to one type of antidepressant but not another type

Differential responses in different subtypes of depression


Treatment-resistant depression

40-50% of patients have inadequate response to an antidepressant

Switch drugs – ensure washout before switching to/from MAOI

Drug combinations: TCA + MAOI sometimes works, but combining MAOI with another antidepressant is risky. SSRI + MAOI combination is not used.

Electroconvulsive therapy

Antidepressants – drug choiceAugmentation

Sometimes the antidepressant effect can be enhanced by combining the antidepressant with a non-antidepressant drug

e.g. lithium

liothyronine (synthetic thyroid hormone)

anticonvulsants


Adverse effects

May vary between individuals


Pre-existing medical conditions

Cardiovascular disease – be careful with TCAs

Neurological disease – consider seizure risk

Obesity, anorexia – TCAs cause weight gain

Interactions with other drugs


Main point:

Choice of antidepressant depends on individual efficacy and side effects, subtype of depressive disorder, pre-existing medical conditions and other drugs being taken.

Antidepressants – adverse effects


Tricyclic antidepressants - TCAs

Muscarinic ACh antagonists: “anticholinergic” side effects

e.g. dry mouth, blurred vision, constipation, urinary retention, tachycardia (high heart rate), memory impairment, sedation



Alpha1-adrenergic antagonists:

Orthostatic hypotension with resultant syncope(fainting when you stand up because of a drop in blood pressure)



H-1 histaminergic antagonists:

e.g. sedation, weight gain



Cardiac arrhythmia – abnormal heart rhythm

(in high doses or with pre-existing heart disease)



Excessive perspiration, sexual dysfunction

(may lead to noncompliance)

Can cause seizures in some people


Monoamine oxidase inhibitors - MAOIs

Anticholinergic (less severe than TCAs)

Sedation (less severe than TCAs)

Cardiac arrhythmia (less severe than TCAs)




Sexual dysfunction is common



Interact with certain foods to cause hypertensive crisis (dangerously high blood pressure)

Some foods contain tyramine, which increases blood pressure, and is normally metabolized by MAO

Aged cheeses, e.g. cheddar, blue cheese are particularly bad and should be avoided

Wensleydale?



Interact with certain drugs to cause hypertensive crisis

Drugs that increase synaptic monoamines and sympathomimetic drugs should be avoided

Includes other antidepressants and over-the-counter flu medications


Selective serotonin reuptake inhibitors - SSRIs

nausea vomiting diarrhea

Sexual dysfunction

headache insomniafatigue



Main points:TCAs have a lot of side effects

MAOIs have dangerous food and drug interactions

SSRIs are safer

How do antidepressants relieve depression?

Molecules(neurotransmitters, receptors, ion channels, transporters)

neurons

synapses

Neural networks

?

Higher cortical function (consciousness, cognition, mood)

Drugs act here

Complex etiology

Genetic component - Multiple genes

Environmental component – stress, neuronal injury

Etiology (causes) of depression

amygdalathalamus

Prefrontal cortex

hippocampus

striatum

Neural network of emotion (greatly simplified)

Limbic System


hypothalamus


Prefrontal cortex (PFC)

Altered blood flow and metabolism in depression

Increased in some parts of PFC; can be reversed with antidepressants

Decreased in other parts of PFC

Decreased metabolism in prefrontal cortex in depression


Amygdala and thalamus

Increased blood flow and metabolism in depression

Can be reversed with antidepressants

Striatum


Reduced blood flow and metabolism in caudate (part of striatum)

Reduced size of caudate


Hippocampus

Stress causes atrophy of hippocampal neurons

Hippocampal volume is decreased in depression


Main point:Depression is often characterized by alterations of function and/or anatomy in brain areas that are involved in emotion.

Some of these alterations are reversed by antidepressants.

Antidepressants -mechanisms of action

Antidepressants – mechanisms of action

Tricyclics inhibit reuptake of norepinephrine and serotonin

Monoamine oxidase inhibitors irreversibly inhibit MAO(moclobemide competitively inhibits MAOA subtype)

Selective serotonin reuptake inhibitors inhibit SERT (serotonin transporter)

Triazolopyridines are 5-HT2A receptor antagonists and inhibit 5-HT reuptake

Bupropion inhibits dopamine and norepinephrine reuptake

venlafaxine inhibits reuptake of norepinephrine and serotonin


Mirtazapine: antagonist of alpha-2 adrenergic autoreceptors and heteroreceptors;effect is increased NE and 5-HT activity


postsynaptic

5-HT15-HT2A 5-HT3-7

5-HT

5-HT1A,1D SERT

5-HTMAO

X

MAOI

X SSRI, TCA,Triazolopyridines

Serotonergic effects

Alpha2 AR

Inhibitory heteroreceptor

Inhibitory autoreceptors

presynaptic

5-HT transporter

MirtazapineX

Triazolopyridines

X


postsynaptic

Beta2 AR

NE

Alpha2 AR NET

NEMAO

X

MAOI

X TCA

Noradrenergic effects

Beta1 AR Alpha2 AR

5-HT1D,2A

Inhibitory heteroreceptors

Inhibitory autoreceptor

presynaptic

NE transporter

Mirtazapine

X

Monoamine depletion hypothesis:

Depression results from reduced availability of 5-HT and/or NE

The monoamine depletion hypothesis predicts that depletion of monoamines causes depression

However…

Depletion of NE by inhibition of tyrosine hydroxylaseor

depletion of 5-HT by tryptophan-free diet

does not cause depression in normal individuals

Patients with depression taking NE selective reuptake inhibitors become depressed if their NE is depleted

Patients with depression taking 5-HT selective reuptake inhibitors become depressed if their 5-HT is depleted

But…

5-HT and NE seem to be required for the maintenance of the antidepressant response

Main point:

Monoamine depletion alone is not sufficient to cause depression

Antidepressants take 2-4 weeks to reach maximum effect.

How is this related to their mechanism of action?

5-HT(-)(+) Postsynaptic

response

No drug

Acute antidepressant (several days)

Chronic antidepressant (4 weeks)

5-HT(+)

5-HT(+)

down-regulation of presynaptic 5-HT1A autoreceptors

down-regulated

5-HT1A

Bigger response

(-)

(-)

5-HT1A

1 2 3 4Weeks of antidepressant treatment

Antidepressant effect

Pindolol: 5-HT1A autoreceptor antagonist

Expected effect of pindolol

Observed effect of pindolol

Main point:

The 2-4 week delay in antidepressant action can be partly (but not completely) explained by down-regulation of presynaptic 5-HT1A inhibitory autoreceptors.

Neurotrophic hypothesis of depression

Beta adrenergic 5-HT4,6,7

GsGs

nucleus

Adenylyl Cyclase

cAMP

Protein kinase A

CREB

BDNF

Increased function and survival of neurons

= up-regulated by antidepressants

Antidepressant effect

Chronic antidepressant treatment results in sustained activation of the cAMP second messenger system, leading to up-regulation of brain-derived neurotrophic factor (BDNF).

Main point:

(other second messenger systems may also be involved)

Hippocampus

hypothalamus

pituitary

adrenal

CRF

ACTH

(-)

glucocorticoids

Xdepression

Other brain areas

CRF

(increased by stress)

(-)

(-)

Release of corticotropin releasing factor (CRF) by the hypothalamus is increased in depressed patients

Main point:

Neurotrophic hypothesis of depressionneuronal function and survival

Stress

glucocorticoids

BDNF

(+)

(+)

(-)

(-)

CRF

(-)

(+)

(+)

hippocampus other brain regions

(+)

Normal state


Stress

glucocorticoids

BDNF

(+)

(-)

CRF

(-)

(+)

Depressed state

(-)

(+)

neuronal function and survivalhippocampus other brain regions

(+) (+)

antidepressants

NE, 5-HT


Stress

glucocorticoids

BDNF

(+)

(-)

CRF

(-)

(+)cAMP(+) (+)

(+)(+)

neuronal function and survivalhippocampus other brain regions

(+)

(-)

(+) (+)


Main point:In susceptible individuals (genetic factors or pre-existing injury) stress causes impaired function and/or atrophy of hippocampal neurons (via inhibition of BDNF release by glucocorticoids). This decreases the ability of the hippocampus to inhibit the release of CRF by the hypothalamus, leading to increased glucocorticoid release. A cycle of CRF disinhibition and atrophy ensues. Altered function and/or atrophy may also occur in other brain areas, via hippocampal connections and/or glucocorticoid/BDNF action.


Main point:

By increasing monoamine levels and stimulating the cAMP second messenger pathway (and possibly other pathways), antidepressants stimulate the release of BDNF, which reverses the neuronal atrophy and restores neuronal function.

“Pharmacology of antidepressants”

The Main Points again

Depression is a disease that has many subtypes

Diagnosis is dependent upon patient interviews and observation of behavior

There are no laboratory tests for depression

Antidepressants alter NE and 5-HT neurotransmission.

Neurotrophic hypothesis

Monoamine depletion hypothesis

pharmacologyofantidepressa.ppt

Health & Medicine

subtype of depression

diagnosis of depression

major depression risk

choice of antidepressant

major depression responsive

basics of depression

variety of antidepressants

nonantidepressant drug