Antidepressant Drugs

Pharmacology 402 February 24, 2010 Mark Hamblin, MD,PhD

Use of Antidepressant Drugs

Major Depression - severe depressive syndrome Dysthymia - milder, chronic condition Bipolar Depression  Resembles major depression, but in an individual with bipolar disorder Depressive syndromes due to medical illnesses e.g. Parkinsons disease Others: anxiety disorders, migraine, pain

Major Depressive Disorder: Not just depressed mood

Changes in thoughts: Loss on interest or pleasure Feelings of worthlessness or guilt Poor concentration, indecisiveness Thoughts about death or suicide Changes in body functions Loss (or gain) of weight or appetite Sleep problems Motor agitation or retardation Low energy Changes are sustained > 2 Weeks, most of the day, almost every day

Depression as an Illness
Mood and physiological/biological changes  Physiology: sleep EEG  Neuroendocrine: Hypothalamus-pituitary-adrenal hormonal system  Anatomic: Brain magnetic resonance imaging (MRI) Clear genetic component  less pronounced than in schizophrenia, bipolar disorder. Multigenic, not Mendelian. Major depressive disorder is heterogeneous = several similar conditions with similar symptoms

Depression: Psychological or Biological?

Likely differs from person to person Generally best thought of as having both components May be incomplete or maladaptive response to stress

Antidepressant Mechanisms

Three General Classes: 1. Amine uptake inhibitors 2. Monoamine oxidase inhibitors 3. Novel antidepressants

Result: rapid

synaptic NE &/or 5-HT

Monoamine Hypothesis of Depression

1960s - 1990s The hypothesis: Major depression caused by a lack of norepinephrine, serotonin, or both (or maybe DA, too) . Treated by correcting this monoamine deficiency.

Why do Antidepressants Take So Long to Work? Not just a simple deficit of 5-HT or NE
 No consistent NE or 5-HT deficits found  Amphetamines, cocaine increase 5-HT & NE, but are not antidepressants Monoamine Hypothesis of Depression (1950s - 1990s: RIP)

Antidepressants: Mechanisms
5-HT, Norepinephrine, (dopamine) Changes in 5-HT, NE, DA receptor stimulation, neuronal activity Changed neuronal sensitivity, growth factors (BNDF), gene expression, cell number & morphology

Minutes

2 - 6 Weeks

Antidepressant effects take time: 2-6 weeks

Major Depression Results in Hippocampal Volume Loss

MacQueen et al., PNAS, 100:1387, 2003

Sheline et al., Am J Psychiatry, 160:1516, 2003

Brain Changes in Depression

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Control of the HPA Axis

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QuickTi r ss t s

) c r ss r t is ictur .

CRF: Corticotrophin Releasing Factor

Key factor in bodys response to stress Released from Paraventricular n. Drives HypothalamicPituitary-Adrenal (HPA) Axis Depression: Increased CRF in CNS

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CRF in Depression
CRF activity increased in depression CRF receptor type 1 antagonists reverse depression-like features in animal models

Classification of Antidepressant Drugs

A. MAO Inhibitors B. Tricyclic Antidepressants (TCAs) C. Selective Serotonin Reuptake Inhibitors D. Novel or Second & Third Generation Drugs
 Maprotiline, Amoxapine, Trazodone  Bupropion  Venlafaxine  Duloxetine  Nefazodone  Mirtazapine

A Serotonergic Synapse

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MAOIs: Site of Action

MAO function
 Inactivation of released NE, 5-HT, DA  First pass metabolism of potentially harmful dietary amines e.g. tyramine

Two forms of MAO

 MAO-A: neurons, liver, gut, placenta
Affinity NE > 5-HT > DA Classic MAO-A Inhibitor: Clorgyline

 MAO-B: neurons, liver, platelets

Affinity Dopamine, Phenylethylamine > 5-HT, Norepinephrine Classic MAO-B Inhibitor: Deprenyl

Currently Used Monoamine Oxidase Inhibitors

H H NH NH2 H H NH2

C C H H

C C CH2

Phenylzine

Tranylcypromine

H C N H H

H N C O N O CH3

H C

H CH3 H N C H C CH

H CH2

Is o carb o x az id

Seleg ilin e

Oral Monoamine Oxidase Inhibitors

Phenelzine (Nardil ) 1959 Tranylcypromine (Parnate ) 1961 Isocarboxazid (Marplan ) 1959, withdrawn 1994, reintroduced by Oxford after 1998 Non-selective:
 Non-selective inhibitors of MAO-A and MAO-B  Affect NE, 5-HT, and DA metabolism

Currently Used Monoamine Oxidase Inhibitors

Irreversible or only very slowly reversible
 Effects last at least 2 weeks after discontinuation

Very effective antidepressants

 Typically 80% response rate for MDD

Brain MAO-A inhibition provides the antidepressant effect

MAOI Side Effects

Potentially Severe: major decline in use Food interaction: Tyramine reaction headache, hypertension, flushing, tachycardia, nausea, stroke, death
 Inhibit the MAOs in all organs  Tyramine in diet cannot be degraded  Tyramine acts as indirect sympathomimetic  Cant eat foods with aged protein: cheese, sauerkraut, pickled herring, beer

Current use of MAOIs

MAOIs still useful May be most potent in severe depression "Atypical" depression: Refractory depression  May work where tricyclics, SSRIs fail Weight, Sleep  May be treatment of choice

Selegiline Patch (Emsam)

Relatively Selective MAO-B Inhibitor Orally: 4% bioavailable Transdermally: 74% bioavailable
 Avoid first pass GI exposure  Much less inhibition of gut & liver MAO-A  Dose is sufficient to inhibit adequate brain MAO-A, yet leave some GI MAO-A intact

Mechanism: probably MAO-A inhibition

Tricyclic Antidepressants 1958 - 1990

Tricyclic Antidepressant Mechanism of Action

All block Norepinephrine (NE) reuptake p Increase synaptic NE concentrations Some have weaker serotonin (5-HT) reuptake blockade p Increase synaptic 5-HT concentrations Require 2 6 weeks to start working.

TCAs: Secondary vs Tertiary Amines

Tertiary -NR2

Secondary -NHR

Tertiary Amines: NE reuptake 5-HT reuptake blockade Secondary Amines: NE reuptake >> 5-HT reuptake blockade

TCA Blockade of Biogenic Amine Uptake

DRUG
Imipramine Desipramine Amitriptyline Nortriptyline Protriptyline Chlomipramine

NE
Moderate Very high Moderate High Very high Moderate

5HT
Moderate Very low Moderate Low Very low High

DA
0 0 0 0 0 0

espite NE/5-HT differences, no overall difference in efficacy.

Blockade of Bacterial Leucine Transporter by a Tricyclic Antidepressant

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TCA Side Effects

Antagonism of specific central & peripheral receptors

 Muscarinic Acetylcholine (anticholinergic)  Dry mouth, constipation, worsen glaucoma, urinary retention, confusion/delirium  Histamine H1 antagonism  Sedation, weight gain  Alpha1 adrenergic antagonism  Orthostatic hypotension

Receptor-Mediated Side-Effects of Tricyclic Antidepressants

Drug

Amine Type Tertiary Tertiary Secondary Secondary Secondary

Anticholinergic

Sedation

Orthostatic Hypotension +++ +++ ++ + +++

Imipramine Amitryptiline Desipramine Nortryptiline Protryptiline

++++ ++++ ++ ++ ++

+++ ++++ ++ ++ +/-

TCA Side Effects

Other Side Effects:  Quinidine like antiarrhythmic  Can cause cardiac conduction delay, heart block  Serious risk of successful suicide by overdose  Ingestion of a two week prescription may be fatal

Tricyclic Antidepressant Efficacy

All are approximately equally effective at appropriate doses (50 70% in most trials) May be more effective than SSRIs in severe depression Some individuals are more responsive to one agent than others: NE vs. 5-HT Selection is mostly on the basis of side effects

Serotonin Selective Reuptake Inhibitors: SSRIs

Fluoxetine (Prozac) 1988 Sertraline (Zoloft) 1992 Paroxetine (Paxil) 1993 Fluvoxamine (Luvox) 1994 Citalopram (Celexa)1998 Lexapro (Escitalopram) 2002

A Serotonergic Synapse

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Serotonin Selective Reuptake Inhibitors: SSRIs

First highly selective 5HT-reuptake blockers Little or no effect on NE reuptake First choice for most depression Clinical efficacy for major depression resembles that of the tricyclics (50 - 70% in most trials)

SSRIs: Effective in Anxiety Disorders & Other Problems

Effective in anxiety disorders:
   

Obsessive compulsive disorder (OCD) Post-Traumatic Stress Disorder (PTSD) Panic disorder Generalized anxiety disorder

And:
 Eating disorders  Premenstrual dysphoric disorder  Social anxiety disorder

SSRI Side Effects

Side effects are less prominent:

 low anticholinergic, antiadrenergic activities  low cardiovascular side effects  low lethality in overdose

SSRI Side Effects

Side effects are still common

       

nervousness, insomnia, anxiety somnolence, loss of drive nausea, diarrhea sexual dysfunction weight loss or gain headaches Neuromuscular excitability (tremor/myoclonus) SSRI withdrawal syndrome with short half-lives  headache, fatigue, insomnia, myalgias

Mechanisms of SSRI Side Effects

Sexual side effects: indirect CNS stimulation of 5-HT2 receptors Gastrointestinal side effects: indirect stimulation of 5-HT3 receptors in the enteric nervous system of the gut

Why choose one SSRI over another?

Mostly very similar: Comparable efficacy, side effects Half-life:  Long: Fluoxetine (Prozac) (3-11 days) - too long  Moderate (~24hr): Sertraline, Paroxetine, Citalopram Long enough, but not too long Weak P450 interactions: Sertraline, Citalopram Individuals may have preferential response or side effects

SSRI/SNRI Discontinuation Syndrome in Adults

F.I.N.I.S.H. Flu-like symptoms: fatigue, muscle aches, headache, diarrhea Insomnia: vivid or disturbing dreams Nausea Imbalance: gait instability, dizziness, lightheadedness, vertigo Sensory disturbance: paresthesia, electric shock sensation, visual disturbance Hyperarousal: anxiety, agitation Onset: 24-72 hours + Resolution: 1-14 days Incidence: ~ 20 - 40 % (who have been treated at least 6 weeks)

SSRI/SNRI Toxicity in Adults

CNS & Neuromuscular: tremor, restlessness, agitation, insomnia, dystonia, hypertonia, dyskinesia, paresthesia, convulsion, congnitive impairment GI: nausea, vomiting, diarrhea Autonomic instability: respiratory distress, tachypnea, hyperthermia, temperature instability, chills, rigors, diaphoresis, tachycardia Onset: variable Resolution: hours to several days

Other Widely Used Drugs

Venlafaxine (Effexor) Duloxetine (Cymbalta) Trazodone (Desyrel) Nefazodone (Serzone) Bupropion (Wellbutrin) Mirtazapine (Remeron)

Venlafaxine (Effexor) 1994 Duloxetine (Cymbalta) 2004

SSRI-Plus: also have weak NE reuptake blockade (quite weak) May be more effective than other SSRIs? Side effects are essentially identical to other SSRIs except increased risk of hypertension Possible increased risk of liver damage (duloxetine)

Bupropion (Wellbutrin)

Mechanism of action: unique, not well understood Active metabolite: 4-hydroxybupropion (CYP2B6) Weak DA, NE uptake blocker Enhances Vesicular Monoamine Transporter-2 (VMAT2) = intraneuronal uptake of dopamine into synaptic vessicles Chronic nicotine may decrease numbers of VMAT2
 ? Related to bupropions action in smoking cessation

Mirtazepine (Remeron) 1996

Novel mechanism: alpha2, 5HT-2, 5-HT3 antagonist Alpha2 blockade: probably contributes to therapeutic effect 5-HT2A antagonism: blocks sexual side effects 5-HT3 antagonism: may block some GI side effects

Mirtazapine Mechanism
Presynaptic alpha2 receptors mediate inhibition of NE release

1. Mirtazapine Takes the brakes off NE activity 2. Alpha1 receptors 5HT neuron activity 3. NE activity leads to 5-HT neuron firing

Mirtazepine (Remeron)

Side effects moderate Sedation: H1 histamine antagonism Weight gain Hypotension: Alpha1, 5-HT2 blockade Moderate anticholinergic activity. Little dopaminergic activity Agranulocytosis - rare but serious ? mechanism

Nefazodone (Serzone) 1995

Structurally and pharmacologically similar to trazodone Like trazodone, mechanism unclear mixed actions on the 5HT system including weak SSRI and 5-HT2A antagonism

Trazodone (Desyrel) 1982

Like Nefazodone, mechanism unclear - weak 5-HT reuptake blocker, 5HT2 partial agonist, alpha1 antagonist May have lower clinical efficacy than other agents Sedation prominent Often prescribed with SSRIs for sedative effect

N N CH2 CH2 CH2 N N

O Cl

The Monoamine Hypothesis Revisited

Drugs promoting increased 5-HT or NE tone have been successful Still many non-responding patients There is a need for alternative agents with alternative mechanisms
? Promotors of neurogenesis ? Other