ANTIDEPRESSANT DRUGS

WHAT ARE ANTIDEPRESSANTS?

Drugs that are used to relieve or prevent psychic depression.

Work by altering the way in which specific chemicals, called neurotransmitters, work in our brains (i.e. in the case of depression, some of the neurotransmitter systems don’t seem to be working properly).

They increase the activity of these chemicals in our brains

The precise cause of affective disorders remains elusive.

Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS, Norepinephrine (NE) and Serotonin (5-HT).

Activity of NE and 5 -HT systems?.

BIOGENIC THEORY OF DEPRESSION

AMINE HYPOTHESIS 1950: Reserpine Induce depression Study: Reserpine depletes storage or

amine neurotransmitters such as serotonin and norepinephrine

Break-through: MAOI and TCA Then: Depression Amine-dependent

synaptic transmission(Antidepressants Amine by means of reuptake and metabolism)

Conclusion: Major model for the subsequent antidepressants, except Buproprion.

MAO

COMT

Amine neurotransmitters areeither degraded (metab)

or reuptaken

Mito

THE PURPOSE OF ANTIDEPRESSANTS IS THE INCREASE OF THE [NEUROTRANSMITTERS] IN THE SYNAPSE

NE SYSTEM Almost all NE pathways in the brain originate from the

cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas (hippocampus, amygdala, hypothalamus, thalamus).

Mood: -- higher functions performed by the cortex. Cognitive function: -- function of cortex. Drive and motivation: -- function of brainstem Memory and emotion: -- function of the hippocampus

and amygdala. Endocrine response: -- function of hypothalamus.

and receptors.

A synapse that uses norepinephrine (NE)

Reuptake of NE

Monoamine oxidase, located on outer membraneof mitochondria; deaminates catecholamines free in

nerve terminal that are not protected by vesicles

Selective inhibitor,reboxetine

Cocaine blocks the NET

Antidepressant

MAO Inhibitors

Stimulant

PO4

Cl-

Cl-

GABACl-

Cl- Cl- Cl- Cl- Cl-

GABA

Out

In

Why does a small amount of stress help you learn better?

But, too much chronic, severe stress DEPRESSION

SEROTONIN SYSTEM As with the NE system, serotonin neurons

located in the pons and midbrain (in groups known as raphe nuclei) send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. --same areas implicated in depression. This system is also involve in:

• Anxiety.• Sleep.• Sexual behavior.• Rhythms (Suprachiasmatic nucleus).• Temperature regulation.• CSF production.

PRESYNAPTICMODULATION

TYPES OF DEPRESSION Major depression Chronic depression

(Dysthymia) Atypical depression Bipolar disorder/Manic

depression Seasonal depression (SAD)

Major depression – recurring and disabling. Symptoms must last for at least two weeks and impair one’s ability to interfere with a person's ability to work, sleep, study, eat, and enjoy once-pleasurable activities.

Chronic depression – less disabling than major depression, but symptoms can last longer, sometimes being unhappy for two years. More common in women, affects 11 million people.

Atypical depression, rather than the other two, is characterized less by pervasive sadness and more by overeating, oversleeping, sensitivty to rejection

Bipolar/manic depression oscillates between major depression and epsidoes of mania (extreme elation), Bipolar I – episode of mania with or without depression. Bipolar II – episode of depression with episode of hypomania or mania.

Seasonal depression (SAD) – often occurs where winters are short or there is a big change in the amount of sunlgiht, and often treated with light therapy.

SYMPTOMS persistently sad, anxious, or empty moods loss of pleasure in usual activities (anhedonia) feelings of helplessness, guilt, or worthlessness crying, hopelessness, or persistent pessimism fatigue or decreased energy loss of memory, concentration, or decision-making

capability restlessness, irritability sleep disturbances change in appetite or weight physical symptoms that defy diagnosis and do not

respond to treatment (especially pain and gastrointestinal complaints)

thoughts of suicide or death, or suicide attempts poor self-image or self-esteem (as illustrated, for

example, by verbal self-reproach)

DIAGNOSIS Extensive patient and family history Blood test for hypothyroidism Current medication DSM-IV

One of the first two symptomsFOUR other symptoms

CAUSES OF DEPRESSION Genetics Death/Abuse Medications

TREATMENT FOR DEPRESSION Psychotherapy Electroconvulsive therapy Natural alternatives

MedicationSSRIsMAOIsTCAsSNRIsNDRIsTeCAs

MONOAMINE OXIDASE (MAO) AND DEPRESSION MAO catalyze deamination of intracellular

monoaminesMAO-A oxidizes epinephrine, norepinephrine,

serotoninMAO-B oxidizes phenylethylamineBoth oxidize dopamine nonpreferentially

MONOAMINE OXIDASE INHIBITORS (MAOIS) History

Isoniazid Iproniazid

Current Drugs Mechanism of Action Side Effects Isoniazid

Iproniazid

MAOIS ON THE MARKET MAO Inhibitors (nonselective)

Phenelzine (Nardil)Tranylcypromine (Parnate) Isocarboxazid (Marplan)

MAO-B Inhibitors (selective for MAO-B)Selegiline (Emsam)

MAOIS MECHANISM OF ACTION MAO contains a

cysteinyl-linked flavin

MAOIs covalently bind to N-5 of the flavin residue of the enzyme

MAOIS SIDE EFFECTS Drowsiness/

Fatigue Constipation Nausea Diarrhea Dizziness Lightheadedness, Decreased urine

output Decreased sexual

function

Sleep disturbances Muscle twitching Weight gain Blurred vision Headache Increased appetite Restlessness Shakiness Weakness Increased sweating

MAOIS SIDE EFFECTS Side effects have put MAOIs in the second

or third line of defense despite superior efficacy

MAO-A inhibitors interfere with breakdown of tyramineHigh tyramine levels cause hypertensive

crisis (the “cheese effect”)Can be controlled with restricted diet

MAOIs interact with certain drugsSerotonin syndrome (muscle rigidity, fever,

seizures)Pain medications and SSRIs must be avoided

TRICYCLIC ANTIDEPRESSANTS (TCAS) History

Imipramine Current Drugs Mechanism of Action Side Effects

Imipramine

Imipramine was first tried as an antipsychoti drug for schizophrenia, proved to be insufficient but proved to have antidepressant qualities, in the 50s around the same time as MAOIs.

Imipramine is very good for severe depression, but it’s almost too good – also causes hypomania and mania

TCAS ON THE MARKET Amitriptyline Desipramine (Norpramin) Doxepin (Sinequan) Imipramine (Tofranil, Tofranil-PM) Nortriptyline (Pamelor) Protriptyline (Vivactil) Trimipramine (Surmontil)

Side effects have made them second line of defense to SSRIs but they are good for treatment resistant depression bc they are so strong.

Amitriptyline – most widely used, most effectve

Desipramine – active metabolite of imipramine, used for neuropathic pain

Doxepin – used for depression and insomnia Imipramine – used for major depression and

enuresis Nortriptyline – same thing Protriptyline – depression UNIQUE BECAUSE IT

IS ENERGIZING rather than sedating Trimipramine – depression, insomnia, and

pain

TCAS MECHANISM OF ACTION TCAs inhibit serotonin,

norepinephrine, and dopamine transporters, slowing reuptake

TCAs also allow for the downregulation of post-synaptic receptors

All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT

TCAS SIDE EFFECTS Muscarinic M1 receptor antagonism -

anticholinergic effects including dry mouth, blurred vision, constipation, urinary retention and impotence

Histamine H1 receptor antagonism - sedation and weight gain

Adrenergic α receptor antagonism - postural hypotension

Direct membrane effects - reduced seizure threshold, arrhythmia

Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)

TCAS SIDE EFFECTS Nonselectivity results in greater side

effects TCAs can also lead to cardiotoxicity

Increased LDH leakageSlow cardiac conduction

High potency can lead to maniaContraindicated with persons with bipolar

disorder or manic depression

TETRACYCLIC ANTIDEPRESSANTS (TECAS) Current Drugs

Mirtazapine (Remeron) Mechanism of Action

Same as TCAs Side Effects

SELECTIVE SEROTONIN REUPTAKE INHIBITORS Most commonly prescribed class Current drugs Mechanism of action Side effects

Serotonin

Also first rationally designed drug class, up until the 70s the antidepressants were sort of found by accident

Serotonin is also referred to as 5-hydroxytryptamine

SSRIS ON THE MARKET citalopram (Celexa) dapoxetine (Priligy) escitalopram (Lexapro) fluoxetine (Prozac) fluvoxamine (Luvox) paroxetine (Paxil) sertraline (Zoloft) zimelidine (Zelmid) (discontinued) indalpine (Upstene) (discontinued)

Fluoxetine 1:1

Sertraline

More trade names once patent is over but I kept original trade names

Citalopram: Major depression Dapoxetine: Premature Ejaculation Escitalopram: Major depression and various other

anxiety disorders Fluxoetine: Major depression, OCD, bulimia, etc Fluvoxamine: OCD Paroxetine: Major depression or anxiety Sertraline: Major depression or anxiety Zimelidine had neurological problems like Guillan

Barre Indalpine had problems with fetal low WBC

SSRIS MECHANISM OF ACTION Exact mechanism remains uncertain Ser-438 residue in the human serotonin

transporter (hSERT) appears to be a determining factor in SSRI potency

Antidepressants interact directly with hSERT

http://www.mayoclinic.com/health/antidepressants/MM00660

SSRIS SIDE EFFECTS Anhedonia Apathy Nausea/vomiting Drowsiness or

somnolence Headache Bruxism

(involuntarily grinding of the teeth)

Extremely vivid and strange dreams

Dizziness Fatigue Changes in sexual

behavior Suicidal thoughts

SSRIS SIDE EFFECTS Many disappear within 4 weeks (adaption

phase) Side effects more manageable compared

to MAOIs and TCAs Sexual side effects are common SSRI cessation syndrome

Brain zapsSexual dysfunction

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS) Slightly greater efficacy than SSRIs Slightly fewer adverse effects than SSRIs Current drugs

Venlafaxine (Effexor)Duloxetine (Cymbalta)

Mechanism of ActionVery similar to SSRIsWorks on both neurotransmitters

Side effectsSimilar to SSRIsSuicide

Venlafaxine 1:1Duloxetine

NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITORS (NDRIS) Current drugs

Bupropion (Wellbutrin) Mechanims of Action

Similar to SSRIs and SNRIsMore potent in inhibiting dopamineAlso anα3-β4 nicotinic antagonist

Adverse effectsLowers seizure thresholdSuicideDoes not cause weight gain or sexual

dysfunction (even used to treat the two)

Bupropion 1:1

SEROTONIN--A KEY PLAYER The overactive point of view

In some depressives CSF 5-HT is elevated Approx. 30% of depressed patients do not

respond to SSRIs Depletion of 5-HT by inhibition of tryptophan

hydroxylase (TH) alleviates depressive symptoms in some patients

Tianeptine, a 5-HT reuptake enhancer that works opposite to SSRIs, is a marketed antidepressant

A selective TH inhibitor shows activity in an animal model of depression

The activation of TH by stress can be blocked by Prozac

CLINICAL PHARMACOLOGY OF ANTIDEPRESSANTS Indications: depression, panic and phobias,

OCD, enuresis, anorexia nervosa, bulimia

Drug Choice: past response, tolerance to side effects, drug-drug interactions

Treatment: 1-6 months; recent report suggests changing if no improvement by 4 weeks

Note: All antidepressants now carry a “black box” warning that they may lead to suicidal thoughts/behavior

SYMPTOMS OF MANIA increased energy

(buying, phoning, sex)

increased gregariousness

pressured speech, talkativeness

decreased sleep drunkenness combative,

dangerous behavior

distractibility racing thoughts impulsive actions

and decisions elevated mood euphoria grandiosity irritability/hostility

(easily angered)

MANIA—too much neurotransmission?

Increased production of inositol phosphate (IP-3) which increases intracellular Ca2+ signalling

Increased DAG which:

activates PKC which phosphorylates a number of substrates including myristoylated alanine rich C kinase (MARCK)

MARCK activates nuclear transcription factors and modulates genes that increase neuromodulatory peptide hormones and alters cell signalling which:

changes neurotransmitter synthesisneuronal excitabiltiysynaptic plasticityneuronal cell loss (prefrontal cortex?)

LITHIUM a monovalent ion that can enter

neurons but is not readily removed.

major mechanism is the reduction of neuronal PI second messenger resulting in reduced response of neurons to ACh and NE

may actually enhance 5-HT

CLINICAL PHARMACOLOGY primary therapy for mania

a narrow therapeutic window (0.8-1.2 meq/L; some guides say 0.6-1.4 meq/L)

absolutely necessary to monitor serum level (trough level approx. 5 days after initial dose)

solely eliminated by kidney, therefore assess patient’s kidney function

ADVERSE EFFECTS tremor decreased thyroid function polydipsia/polyuria edema ECG changes (depression of T-wave) excreted in breast milk

OTHER MEDICATIONS Anticonvulsants: carbamazepine and

valproic acid for rapid cyclers

Olanzepine approved for treatment of mania

St. John’s Wort: questionable efficacy, but high potential for drug-drug interactions

FACTORS INFLUENCING CHOICE

Features of illness, e.g. agitation, hypersomia

Suicide risk Other therapy Other illness. Side effects Cost Special problems

e.g. Age, driving, pregnancy

DRUG FAILURE Non compliance. Inadequate dosage. Other drugs e.g. alcohol, caffeine. Unresolved outside problems. Up to 26% failure even if above don’t

apply.

ADJUVANTS AND COMBINATIONS

Realm of specialists

Lithium, carbamazepine

Mixtures i.e. SSRI and TCA

Dangerous – need expert supervision

NEUROENDOCRINE THEORY Depression is associated with elevated

plasma cortisol level that is due to excessive release of hypothalamic CRH.

  This elevated CRH may reflect defective

monoamine transmission. N.B hypothalamic neurons controlling

pituitary function receive noradrenergic and serotonergic inputs which control their discharge

This theory is supported by: High CRH concentration in brain & CSF

in depressed patients High plasma cortisol level in depressed

patients CRH injected into brain of experimental

animals gives symptoms like that of depression

Cushing’s syndrome is often associated with depression

 

NEURODEGENERATION THEORY Major depression may be associated

with neurodegeneration in the hippocampus & prefrontal cortex and antidepressants may act by inhibiting or actually reversing this loss by stimulating neurogenesis

This theory is supported by: Imaging studies showed shrinkage of hippocampus &

prefrontal cortex of depressed patients Functional imaging reveals reduced neural activity in these

regions Antidepressants promote neurogenesis in these regions and

restore functional activity Preventing hippocampal neurogenis in depressed rats

prevents the behavioral effects of antidepressants

Antidepressants increase the production of brain derived neurotrophic factor (BDNF) which promotes neurogenesis and protects neurons against apoptosis