Depression and Anti-depressants

By,

Devansh Mehta

M.Pharm.(Pharmacology)

M.B.A.(Pharmaceutical marketing and Hospital Administration)

B.Pharmacy

Coordinates: +91-8171552727, devanshmehta.pharma@gmail.com

Major depression and mania are two extremes of affective disorders which refer to a pathological change in mood state.

Major depression is characterized by symptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetite or sleep, melancholia, suicidal thoughts, etc.

Mania refers to elation or irritable mood, racing thoughts, accelerated speech, increased activity, reduced sleep, reckless or violent behavior and may be progressive loss of contact with reality.

 You might have this type if you feel depressed most of the time for most days of the week

Some other symptoms you might have are:

Loss of interest or pleasure in your activities

Weight loss or gain

Trouble getting to sleep or feeling sleepy during the day

Feelings of being "sped up" or "slowed down"

Being tired and without energy

Feeling worthless or guilty

Trouble concentrating or making decisions

Thoughts of suicide

Persistent Depressive Disorder

If you have depression that lasts for 2 years or longer, it's called persistent depressive disorder. It used to be known as dysthymia.

You may have symptoms such as:

Change in your appetite (not eating enough or overeating)

Sleep too much or too little

Lack of energy, or fatigue

Low self-esteem

Trouble concentrating or making decisions

Feel hopeless

Bipolar Disorder

Someone with bipolar disorder, which used to be called "manic depression," has mood episodes that range from extremes of high energy with an "up" mood to low "depressive" periods.

When you're in the low phase, you'll have the symptoms of major depression.

Medication can help bring your mood swings under control. Whether you're in a high or a low period, your doctor may suggest a mood stabilizer, such as lithium.

Seasonal Affective Disorder (SAD)

Seasonal affective disorder is a period of major depression that most often happens during the winter months, when the days grow short and you get less and less sunlight.

If you have SAD, antidepressants can help. So can light therapy. You'll need to sit in front of a special bright light box for about 15-30 minutes each day.

Psychotic Depression

People with psychotic depression have the symptoms of major depression along with "psychotic" symptoms, such as:

Hallucinations (seeing or hearing things that aren't there)

Delusions (false beliefs)

Paranoia (wrongly believing that others are trying to harm you)

A combination of antidepressant and antipsychotic drugs can treat psychotic depression. ECT may also be an option.

Postpartum Depression

Women who have major depression in the weeks and months afterchildbirth may have postpartum depression. Antidepressant drugs can help.

Premenstrual Dysphoric Disorder (PMDD)

Women with PMDD have depression and other symptoms at the start of their period.

Besides feeling depressed, you may also have:

Mood swings

Irritability

Anxiety

Trouble concentrating

Fatigue

Change in appetite or sleephabits

Feelings of being overwhelmed

'Situational' Depression

This isn't a technical term in psychiatry. But you can have a depressed mood when you're having trouble managing a stressful event in your life, such as a death in your family, a divorce, or losing your job. Your doctor may call this "stress response syndrome."

Psychotherapy can often help you get through a period of depression that's related to a stressful situation.

Atypical Depression

This type is different than the persistent sadness of typical depression. If you have atypical depression, a positive event can temporarily improve your mood.

Other symptoms of atypical depression include:

Increased appetite

Sleeping more than usual

Feeling of heaviness in your arms and legs

Oversensitive to criticism

Classification of Anti-depressants

1. Reversible inhibitors of MAO – A : Moclobemide, Clorgyline

2. Tricyclic Antidepressants

NA + 5 HT reuptake inhibitors: Imipramine, Amitriptyline, Trimipramine, Doxepin, Dothiepin, Clomipramine

Predominantly NA reuptake inhibitors: Desipramine, Nortryptyline, Amoxapine

Selective serotonin reuptake inhibitors: Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram

Atypical Antidepressants: Trazodone, Mianserin, Mirtazapine, Venlafaxine, Tianeptine, Amineptine, Bupropion

MAO - inhibitors

MAO is a mitochondrial enzyme involved in the oxidative deamination of biogenic amines (Adr, NA, DA, 5-HT). Two isoenzyme forms for MAO have been identified.

MAO –A: Preferentially deaminates 5 –HT and NA, and is inhibited by clorgyline, moclobemide.

MAO – B: Preferentially deaminates phenylethylamine and is inhibited by selegiline.

Their distribution also differs. Peripheral adrenergic nerve endings, intestinal mucosa and human placenta contain predominantly MAO –A, while MAO-B predominates in certain areas of brain and in platelets. Liver contain both isoenzymes.

Reversible Inhibitors of MAO-A

Moclobemide: It is a reversible and selective MAO – A inhibitor with short duration of action; full MAO activity is restored within 1-2 days of stopping the drug.

Because of competitive enzyme inhibition, tyramine is able to displace it – potentiation of pressor response to ingested amines is weak, dietary restrictions are not required.

Dose : 150 mg BDS- TDS (max: 600 mg/ day)

Tricyclic Antidepressants

Imipramine, a dibenzazepine was found during clinical trials in 1958 to selectively benefit depressed but not agitated psychotics.

In contrast to CPZ, it inhibited NA and 5 – HT reuptake into neurons.

A large number of congeners were soon added and are collectively called Tricyclic Antidepressants.

The TCA’s inhibit monoamine uptake and interact with a variety of receptors viz. muscarinic, Alpha adrenergic, histamine H1, 5-HT1, H-HT2. and occasionally dopamine D2.

However, relative potencies at these sites differ among different compounds.

The newer selective serotonin reuptake inhibitors SSRI’s and atypical antidepressants interact with fewer receptors and have more limited spectrum of action.

Mechanism of Action

The TCA’s and related drugs, inhibit active uptake of biogenic amines NA and 5-HT into their respective neurons and thus potentiate them.

They, however, differ markedly in their selectivity and potency for different amines.

Most of the compounds donot inhibit DA uptake, except bupropion.

Moreover, amphetamine and cocaine are strong inhibitors of DA uptake. However, it has been proposed that TCA’s indirectly facilitate dopaminergic transmission in forebrain that may add to the mood elevating action.

Uptake inhibition results in increased concentration of the amines, in the synaptic cleft in the CNS and periphery. Tentative conclusions drawn are:

Inhibition of DA uptake correlates with stimulation action, but is not primarily involved in anti-depressant action.

Inhibition of NA and 5-HT uptake is associated with antidepressant action.

Effects on Body System

1. CNS: Effects differ in normal individuals and the depressed.

In normal individuals it induces a peculiar clumsy feeling, tiredness, light headedness, sleepiness, difficulty in concentrating and thinking, unsteady gait. These effects tend to provoke anxiety,

There is no mood elevation or euphoria, effects are rather unpleasant and may become more so on repeated administration.

In depressed patients little acute effects are produced, except sedation. After 2-3 weeks of continuous treatment the mood is gradually elevated, patients become more communicative and start taking interest in self and surrounding.

ANS: Most tricyclic antidepressants are potent anticholinergics-cause dry mouth, blurring of vision, constipation and urinary hesitancy as side effect.

CVS: Effects on cardiovascular function are prominent, occur at therapeutic concentrations and may be dangerous in overdose.

Tachycardia: due to anticholinergic and NA potentiating actions.

Postural hypotension: Due to inhibition of cardiovascular reflexes and Alpha 1 blockade.

Selective Serotonin Reuptake Inhibitors

The major limitations of standard TCA’s are,

Frequent anticholinergic, cardiovascular and neurological side effects.

Relatively low safety margin, hazardous in overdose, fatalities common.

Lag-time of 2-4 weeks before antidepressant action manifests

Significant number of patients respond incompletely and some donot respond

To overcome these shortcomings a large number of newer antidepressants have been developed since 1980’s. The most significant of these are the SSRI’s.

Though, none of the newer drugs has surpassed older TCA’s in overall efficacy, some patients not responding to one type of drug may respond to the other.

A new constellation, of mild side effects, viz, nervousness, restlessness, insomnia, anorexia, dyskinesia, headache and diarrhea is associated with them, but patient acceptability is good.

The SSRI’s inhibit drug metabolizing isoenzymes CYP2D6 and CYP3A4, elevate plasma levels of TCA’s, haloperidol, clozapine, terfenadine, astemizole, warfarin, Betal blockers and some BZD’s and carbamazepine.

The overall antidepressant efficacy of SSRI’s is similar to that of TCA’s, though some patients not responding to one may respond to the other.

Because of freedom from psychomotor and cognitive impairment, SSRI’s are preferred for prophylaxis of recurrent depression.

Fluoxetine: A bicyclic compound, prototype of the SSRI’s and the longest acting, plasma t ½ is 2 days and that of its active demethylated metabolite is 7-10 days.

Other drugs are Fluvoxamine, Paroxetine, Sertraline, Cetalopram

Atypical Antidepressants

1. Trazodone: It is the first atypical antidepressant, selectively but less efficiently blocks 5-HT uptake and has prominent Alpha blocking as well as weak 5 –HT2 antagonistic action. It is sedative but not anticholinergic, causes bradycardia, rather than taxchycardia, does not interfere with intracardiac conduction-less prone to cause arrhythmia-better suited for the elderly.

Other drugs are Mianserin, Tianeptine, Amineptine, Venlafaxine, Mirtazapine, Bupropion, Nefazodone.

Venlafaxine: A novel antidepressant referred to as serotonin and noradrenaline reuptake inhibitor (SNRI), because it inhibits uptake of both these amines but, in contrast to older TCA’s does not interact with cholinergic adrenergic or histaminergic receptors or have sedative property.

Uses

1. Endogenous Depression (Major depression)

2. Obsessive-compulsive and phobic states

3. Anxiety Disorders

4. Neuropathic pain

5. Attention deficit hyperactive disorder

6. Enuresis

7. Migraine

8. Pruritus

Antimanic Drugs

Lithium is a small monovalent cation. In 1949 it was found to be sedative in animals and to exert beneficial effects in manic patients. It was tried sporadically but failed to gain popularity because,

Response was slow and poorly measurable

Use without monitoring serum levels was associated with unacceptable toxicity

At present Li is a drug of its own kind to exert a prophylactic effect in bipolar manic depressive illness and is being extensively used at centres where its serum levels can be measured. Over the part 2 decades the antiepileptics carbamazepine and valproate have emerged as alternatives to Li, their mood stabilizing property has been established now.

Actions and Mechanism

CNS: Lithium has practically no acute effects in normal individuals.

The mechanism of antimanic and mood stabilizing action of Li is not known. It has been proposed that,

A) Li partly replaces body Na+ and is nearly equally distributed in and outside the celsl, this may affect ionic fluxes across brain cells or modify the property of cellular membranes.

B) Li has been found to decrease the release of NA and DA in the brain of treated animals without affecting 5 – HT release.

Uses

Acute manic episode

Prophylaxis in bipolar disorder

Major depression

Cancer chemotherapy

Inappropriate ADH secretion syndrome