Anti Depression

PRESENTED BY: PARTH KHANDHERIA

M.PHARM SEM-2

DEPARTMENT OF PHARMACOLOGYL.M. COLLEGE OF PHARMACY

AHMEDABAD.

CONTENTSDefinitionEpidemiologyAetiologyHypothesisSymptomsDiagnosisAntidepressantsReferences

Depression

WHO Definition

“Depression is a common mental disorder characterized by sadness, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness, and poor concentration”

Epidemiology of depression

Depression is a major cause of morbidity worldwide.Lifetime prevalence varies widely,3% in Japan 17% in the US.

In most countries the number of people who would suffer from depression during their lives falls within an 8–12% range.

Rank 1 2 3 4 5 198

Country USA Nepal East

TimorBangladesh India Japan

Higher rates of depression are found in women,with report suggesting that women are twice as likely as men to suffer depression.

Average age of onset of depression is in the late 20s.

Aetiology of depression

Depression Hypothesis

1. Neurotransmitters & Catecholamine Hypothesis

2.Receptor Sensitivity Hypothesis3.Permissive Hypothesis4.Electrolyte Membrane Hypothesis5.Neuroendocrine Hypothesis

1 Neurotransmitters & Catecholamine Hypothesis

Smaller amount of neurotransmitters causes depression Depression is caused by a functional deficiency of

catecholamines, particularly norepinephrine (NE)

i. MAO HYPOTHESISii. SERETONIN HYPOTHESISiii.DOPAMINE HYPOTHESIS

MAO HYPOTHESIS

Blocking the action of MAO leads to an increased availability of neurotransmitters.

MAO-A oxidizes epinephrine, norepinephrine, serotonin -MAO-B oxidizes phenylethylamine -Both oxidize dopamine nonpreferentiallyMAO inhibitors are Dopamine-Epinephrine-

Norephinephrine-Seratonin agonists.This theory is based on the ability of the monoamine

oxidase-A inhibiting drugs to facilitate NE/5-HT neurotransmission and to act as effective antidepressant drugs.

SERETONIN HYPOTHESIS

Depression is caused by a functional deficit of NE and /or 5-HT, at certain sites in brain.

which inhibit the storage of 5-HT and NE, which increase 5-HT synthesis elevates mood. Therefore, it was reasoned that depression must be

associated with a decreased NE/5-HT neurotransmission.

But the serotonin-only theory has shortcomings: it does not explain the role of noradrenaline in

depression

DOPAMINE HYPOTHESIS DA receptor agonists have some antidepressant effects

in at least subgroups of patients. A number of antidepressant drugs also have DA agonist activities.

Neuroleptic medications that are known to block DA receptors and used to treat psychosis are not generally associated with the induction of depression. It is more likely that other, primary pathophysiological processes impact on dopaminergic systems, especially in more severe, psychotic forms of affective illness.

2.Receptor Sensitivity Hypothesis

Supersensitivity(An extreme and high degree of sensitivity to a drug or chemical) and up-regulation(An increase in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent) of post-synaptic receptors leads to depression

Suicidal and depressed patients have increased 5HT-α2

receptors

3.Permissive Hypothesis The control of emotional behavior results from a balance

between noradrenaline and serotonin. According to this theory, the depressive phase is

characterized by low central serotonin function. The Permissive Hypothesis postulates that low levels of

serotonin permit abnormal levels of noradrenaline to cause depression.

If serotonin cannot control noradrenaline, and noradrenaline falls to abnormally low levels, the patient becomes depressed

According to this hypothesis, antidepressant drugs(serotonin-noradrenaline reuptake inhibitors (SNRIs) are effective to the degree that they reinstate the ability of serotonin to control noradrenaline, thus restoring the critical balance that controls emotional behavior.

4.The Electrolyte Membrane Hypothesis

Lithium-sodium counterflow mechanism in red cells has been described and protein structural differences between patients with bipolar-polar disorder and controls have been revealed. The mechanism of action of lithium in bipolar disorder is still not understood.

5.The Neuroendocrine Hypothesis.

According to this hypothesis, pathological mood states are explained by altered endocrine function.

This theory historically grew out of observations that altered mood states were associated with thyroid or Cushings disease.

Current explorations of pathophysiology using neuroendocrine theories have tended to result in research tools such as the dexamethasone suppression test becoming diagnostic tools.

Symptoms Associated With

Depression

DIAGNOSIS

Lab tests-Doctor may do a blood test called a complete blood count or test your thyroid to make sure it's functioning properly.

DSM-V(Diagnostic and Statistical Manual of Mental Disorders) Your mental health professional may use the criteria for depression listed in the Diagnostic and Statistical Manual of Mental Disorders , published by the American Psychiatric Association. This manual is used by mental health providers to diagnose mental conditions and by insurance companies to reimburse for treatment.

Electroconvulsive therapy (ECT) is a procedure, done under general anesthesia, in which small electric currents are passed through the brain, intentionally triggering a brief seizure. ECT seems to cause changes in brain chemistry that can quickly reverse symptoms of certain mental illnesses

vagal nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to thevagus nerve. It is used as an adjunctive treatment for certain types of intractable epilepsy and treatment-resistant depression.

ANTIDEPRESSANTS CLASSIFICATION

1ST generation Tricyclic

Antidepressants-Imipramine, amitriptyline, clomipramine, doxepin

MAO inhibitors-• Reversible-

moclobomide, clorgyline.

• Irreversible-phenelzine, tranylcypromine, isocarboxazid.

2nd generation(Atypical)

Selective Serrotonin Reuptake Inhibitors (SSRIs)- fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram

Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)- venlafaxine, desvenlafaxine,

Tricyclic Antidepressants (TCAs) Chemical structure contains three rings. Most of the TCAs block SERT & NET, increasing the

monoamine levels & contributing to the antidepressant Effect.

Pharmacological propertiesi. Block presynaptic NE reuptake transporterii. Block presynaptic 5-HT reuptake transporteriii.Block postsynaptic histamine receptorsiv.Block postsynaptic ACh receptors

TCA’S 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)

Pharmacokinetics Well absorbed upon oral administration Relatively long half-lives Metabolized in the liver Converted into intermediates that are later detoxified Readily cross the placenta

Clinical Limitations of TCA’s Slow onset of action Wide variety of effects on CNS (adverse side effects): Can directly impair attention, motor speed, dexterity,

and memory Cardiotoxic and potentially fatal in overdoses

Clinical uses of TCA

for moderate to severe endogenous depression, especially with psychomotor features such as insomnia (a sedating drug such as amitriptyline is used) or poor appetite

for panic and related disorders (e.g. clomipramine ) for neuropathic pain (e.g. postherpetic and other forms

of neuralgia )

MONOAMINE OXIDASE INHIBITORS

Most antidepressant MAOIs act on both forms of MAO, but antidepressant activity, as well as the main side effects of MAOIs, is associated with MAO-A inhibition.

MAO is located intracellularly, mostly associated with mitochondria, and has two main functions.

Within nerve terminals, MAO regulates the free intraneuronal concentration of noradrenaline or 5-HT, and. It is not involved in the inactivation of released transmitter.

MAO is important in the inactivation of endogenous and ingested amines that would otherwise produce unwanted effects.

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Side effects:- Hypotension Excessive central stimulation may cause tremors, excitement,

insomnia and, in overdose, convulsions. Increased appetite, leading to weight gain, can be so extreme as

to require the drug to be discontinued. Atropine-like side effects (dry mouth, blurred vision, urinary

retention, etc.)

Selective Serrotonin Reuptake Inhibitors (SSRIs)

2nd generation antidepressant drug SSRIs are now considered to be the first line of drugs in

the treatment of depression All SSRIs inhibit the serotonin transporter and block the

reuptake of serotonin into the neuron, hence increasing the levels of serotonin at the synapse.

Ser-438 residue in the human serotonin transporter (hSERT) appears to be a determining factor in SSRI potency

Antidepressants interact directly with hSERT

Advantages of SSRIs over TCAs

To overcome the shortcomings of TCAs newer drugs such as SSRIs were developed

Major advantages of SSRI were Negligible anticholinergic side effects They produce little or no sedation at all Postural hypotension do not occur Low CVS side effects, no arrhythmias No effect on cognition/ psychomotor functions Do not lower seizure threshold Safer in overdose Faster acting than TCAs No complaints of weight gain Better compliance

Pharmacokinetic

well absorbed plasma half-lives of 15-24 hours (fluoxetine is longer

acting: 24-96 hours). Paroxetine and fluoxetine are not used in combination

with TCAs, whose they inhibit hepatic metabolism of TCA, so increasing TCA toxicity.

Side effects

Nausea, anorexia, insomnia, loss of libido In combination with MAOIs, SSRIs can cause a

'serotonin syndrome' characterized by tremor, hyperthermia and cardiovascular collapse, from which deaths have occurred.

Not recommended for treating depression in children under 18, in whom efficacy is doubtful and adverse effects, including excitement, insomnia and aggression in the first few weeks of treatment, may occur. The possibility of increased suicidal ideation is a concern in this age group.

Serotonin syndrome At high doses or combined with other drugs an

exaggerated response can occur This is due to increased amounts of serotonin Alters cognitive function, autonomic function and

neuromuscular function Potentially fatal

Serotonin withdrawal syndrome With discontinuation of any SSRI onset of withdrawal

symptoms occur within a few days and can persist 3-4 weeks

Symptoms: disequilibrium, gastrointestinal problems, flu-like symptoms, sensory disturbances, sleep disturbances

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIS)

• Slightly greater efficacy than SSRIs• Slightly fewer adverse effects than SSRIs• Current drugs

– Venlafaxine (Effexor)– Duloxetine (Cymbalta)

• Mechanism of Action– Very similar to SSRIs– Works on both neurotransmitters

• Side effects– Similar to SSRIs– Suicide

Norepinephrine Dopamine Reuptake Inhibitors (NDRIS)

Current drugsBupropion (Wellbutrin)

Mechanims of Action Similar to SSRIs and SNRIs More potent in inhibiting dopamine Also anα3-β4 nicotinic antagonist

Adverse effects Lowers seizure threshold Suicide Does not cause weight gain or sexual dysfunction (even

used to treat the two)

New Drug Treatments

• COMT inhibitors – second of two enzymes that catalyze the inactivation of DA and NE by decreasing neurotransmitter levels– Tolcapone – specific inhibitor of COMT used in

treatment of Parkinson’s• SNRI – soon to be available for clinical use

– Reboxetine – first of its kind to block NE reuptake without also blocking DA or 5-HT reuptake

• Serotonin 5-HT1 Agonists – appear to be responsible for acute antidepressant effects

• DHEA – a major glucorticoid hormone secreted by the adrenal glands, function unclear– Precursor to estrogen and testosterone– Increases feelings of physical and psychological well-

being• SAM, SAMe – plays key intermediary role in many

metabolic reactions that involve the transfer of the methyl groups between molecules– Not generally recommended for treatment of depression

ReferencesPharmacology by Rang H.P, Dale M.M, 6th edition,2007

Tripathi K.D, Essentials of Medical Pharmacology, 6th Edition, Jaypee brother publisher, New Delhi,

http://www.webmd.com/depression/http://pn.psychiatryonline.org/content/41/24/21.fullhttp://www.mayoclinic.com/health/maois/MH00072http://www.Medscape.org

Myth:

Hard Work Beats Depression

It's Not a Real Illness

Depression Is Just Self-Pity

Help Means Drugs for Life

Depressed People Cry a Lot

Depression Is Part of Aging

Talking Makes Things Worse

Teens Are Unhappy by Nature

Depression Is Tough to Treat

Fact:Anyone Can Get Depressed

It Can Sneak Up Slowly

Family History Is Not Destiny

Positive Thinking May Help

Exercise Is Good Medicine

Hope for Better Days Is Real