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Depression – causes and treatment

Depression accounts for high degree of morbidity with rates higher among females during their reproductive years but after the age of 50-60 years, the incidence is equal among both the sexes. It is a common and serious illness which affects 5- 10% of the general population at any time.

Classically a patient of depression has feelings of worthlessness, vague complaints related to various parts of body, loss of sleep and appetite, lack of energy and excessive fatigue.

Generally it has been divided into Reactive and Endogenous depression. Patients suffering reactive type have a clear precipitating cause such as death of a loved one, marital discord, and failure in exams, financial loss and loss of employment.

It is fluctuating type and the patient often has a vulnerable personality while case of endogenous depression suffers from a feeling of profound guilt and variations in mood. There is no obvious precipitating cause and these people suffer from a form of morbid personality. Most patients suffer from a mixture of both forms.

depression

DIAGNOSTIC CRITERIA FOR MAJOR DEPRESSIVE EPISODE (DSM-III-R)

1. Persistent depressed mood most of the day and nearly every day.

2. Decreased interest or pleasure in all or almost all activities most of the day nearly every day.

3. Significant weight change.

4. Insomnia or hypersomnia almost daily

5. Psycho-motor retardation or agitation.

6. Fatigue or loss of energy.

7. Feelings of worthlessness.

8. Diminished ability to think or concentrate.

9. Recurrent thought of death / suicidal attempts / suicidal ideation.

At least 5 of the above symptoms are present over the same 2 week period nearly every day. Symptoms are not due to ionic mental disorder or bereavement.

Etiology and patho-physiology

A number of factors ranging from genetic, environmental factors to neuro chemical abnormalities have been incriminated in the pathogenesis of depression.

Genetic

There is a possible genetic predisposition and first degree relatives of patient have a higher risk. There is growing evidence that bipolar disorders have specific gene markers associated with affective disorders. But it cannot be denied that genetic factors are stronger in bipolar disorder than in unipolar type.

Neuro transmitter system

There is hypothesis that neurotransmitters like nor epinephrine, serotonin and dopamine play important role in causing it and mania. It is either the deficiency or excess of these substances at important sites in the brain which accounts for depression. Relative functional under activities of neuro transmitters and down regulation of post synaptic receptors have also a role.

It is also associated with decreased monoamine activity (decreased synthesis, increased degradation or altered synaptic function). Some depressed patients show reduced levels of 24 hrs excretions of urinary MHPG (3-methoxy 4- hydroxyphenylglycol) and the catalytic enzyme dopamine B-hydroxylase.

Environmental factors

There is an overall temporal relationship between stressful and negative life events such as loss of job, death of spouse, marked change in social, and even assault on self esteem which have bearing on the development of an affective episode. Environments of any individual, plays important role in the causation of it.

Neuro endocrinal factors

It is known to influence hypothalamic pituitary adrenal thyroid axis. An important effect of depression is on cortisol. Depressed patients have elevated levels of 24 hour unitary free cortisol, increased secretary episodes and disrupted system of cortisol production.

Biological abnormalities

Depressed patients have sleep abnormalities in the form of early morning awakening and decreased sleep efficiency. As many as 80 to 85% of depressed patients have sleep discontinuity and remaining 15 to 20% show hypersomnia.

There is shortened REM latency period. Patients of endogenous type show REM latency of 40 to 50 minutes as compared to 90 minutes in normal individual. Thus changes in sleep rhythm, EEG and particularly shortening of REM latency are important biological markers in cases of depression.

Clinical features

1. Apparent sadness I unhappy / depressed mood.

2. Inner tension

3. Reduced sleep / insomnia early and late.

4. Reduced / loss of appetite

5. Concentration difficulties

6. Lassitude

7. Inability to feel / loss of interest in surroundings

8. Pessimistic thoughts

9. Suicidal thoughts

10. Agitation

11. Depersonalization

12. Paranoid symptoms (delusions / ideas of persecution)

13. Loss of weight

14. Hypochondriasis (Preoccupation with self. Frequent complaints)

Adapted from Hamilton & Montgomery depression rating scale

Treatment

It is both psychological; inter personal, cognitive behavior therapy and pharmacotherapy. Patients are beset with impairment of various kinds throughout their lives and here include cognitive impairments (problem of memory and concentration) mood instability and increased risk of substance abuse which is often accompanied by violence, homicide and even suicidal tendencies.

Most of these disorders have strong tendencies for recurrence. It is important to detect the impending illness at the earliest. Psychological therapies such as reassurance and sympathy have their role in managing cases of depression provided these are done under the supervision of a trained psychiatrist.

Pharmacotherapy

Anti depressants are the mainstays of treatment. These should not be used for the initial treatment of mild type but should be offered to patients with moderate to severe form of depression.

Patients with mild depression respond to interventions such as advice on sleep, hygiene, brief CBT and counseling sessions. For moderate to severe, structured psychological interventions are effective. CBT is also employed.

Commonly used drugs include Tricyclic (TCA) and monoamine oxidase (MAO) inhibitors. These dmgs are effective in the treatment of clinical syndromes of major kind. The major tricyclic anti depressants include Amitriptyline, Imipramine and Doxepine while MA oxidase inhibitor are Pheneizine, Isocarboxazid. Newer anti depressants include clomipramine, fluoxetine, trazodone, trimipramine, sertaline Hydrochloride etc. Let us look at some of the important anti depressants used in clinical practice.

Tricyclic Anti depressants

These inhibit active uptake of biogenic amines and 5-HT into their respective neurons and thus potentiate them and this is associated with anti depressant action. The effect is noticed after 3-4 weeks of administration.

Imipramine

It is a dibenzapine analogue of phenothiazine and is selectivity beneficial to depressed but not agitated psychotics. Dose 25 mg 2-3 times a day increased every week till under control. Maximum dose 200 mg/day.

Amitriptyline

It blocks the neither neuronal uptake nor adernaline and exerts anticholineigic activity. It is converted to a neither active metabolite nor tripyline and its beneficial effect starts in 2-3 weeks. It is more suitable for patients of depression showing anxiety and agitation. 10-25 mg three times a day and increased to maximum of 150-300 mg per day.

Clomipramine

It is metabolized in liver to nor clomipramine which contributes to its noradrenergic activity. It is effective in endogenous kind. 10-25 mg per day gradually increasing to 100-120 mg per day according to response. Maximum dose 250 per day.

Doxepin

It is a highly selective 5 HT uptake inhibitor and has a quicker onset of anti depressant action. 25 mg three times a day gradually increasing to 200 mg per day. Max 300 mg per day.

Dothiepin

It acts to inhibit dopamine uptake besides NA and 5-HT at neuronal endings. MAOIs potentiate its action hence should not be given concurrently or within 14 days of stopping MAOI: Dose 25 mg 2-3 times a day increasing gradually upto a maximum ofl50mgaday.

Nortriptyline

It is a predominantly NA uptake inhibitor and is of use in all types. Dose 75-150 mg per day upto a maximum of 250 mg per day.

Side effects of tricyclic anti-depressants

These include day mouth, constipation, blurred vision, changes in accommodation, palpitation, tachycardia, tremors, dizziness, orthostatic hypotension, weakness, fatigue, ataxia, alleigic skin reftctions, blood sugar changes, mania, schizophrenia etc.

MONO-AMINE OXIDASE INHIBITORS (MAOIS)

MAO is a mitochondrial enzyme involved in the oxidative deamination of biogenic amines (Adr NA, DA, 5 HT). MAO inhibitors reverse this action.

Moclobemide

This dmg has short duration of action and lacks anti cholinergic, cognitive, psychomotor and cardivascular side effects of TCAs. It is safer in elderly patients. Dose 150 mg 2- 3 times a day upto maximum of 600 mg a day. Side- effects include dizziness, nausea, headache, insomnia. It may cause liver damage.

Selective serotonin reuptake inhibitors (SSRIs). These block neuronal transport of serotonin immediately leading to complex secondary responses on 5 HT2 receptors. They are relatively safe and are 1st line of drugs in depression. These have little or no sedation do not interfere with cognitive and psychomotor functions or produce anticholinergic side-effects.

(a) Fluoxetine hydrochloride. Its antidepressant action is linked to its inhibition

of CNS neuronal uptake of serotonin. 10-20 mg once a day, can be increased upto 60 mg per day.

(b) Fluvoxamine. It is a shorter acting SSRI. 300 mg per day.

(c) Paroxetine. It is other short acting SSRIs. Oral bioavailabiity is 50%. 20-40 mg per day (maximum 50 mg per day).

(d) Sertraline hydrochloride. It is a potent selective serotonin reuptake inhibitor (SSRI) and is mainly indicated in major depressive disorders. 50-100 mg per day gradually increasing to 100-200 mg per day.

(e) Citalopram. It selectively inhibits the reuptake of serotonin into synaptic terminals thus potentialing serotonergic neurotransmission used for treatment of depressive illness in initial phase and as maintenance against relapse. Dose 20-40 mg once a day (Maximum 60 mg once a day).

Side effects of SSRIs

Anorexia, nausea and diarrhea. They may interfere with sexual functions.

TETRICYCLIC ANTI DEPRESSANTS

MIANSERIN

It has a pronounced presynaptic alpha 2 adreneigic blocking action and may increase NA release from neurons in brain. Mainly indicated in psychotic and neurotic depression. Dose 30-60 mg per day in divided doses. Side effects include sedation, fatigue. May cause hypotension and precipitate seizures.

TRIAZOLOPYRIDINE

Trazodone

It acts by blocking alpha-2 auto (on NA neurons) and hetero (on 5-HT neurons) receptors enhancing both NA and 5 NT release. Selective enhancement of anti-depressive 5-NT receptor action is achieved by concurrent blockade of 5-HT2 and 5- HT3 receptors. It has weak anti cholinergic action and low propensity to cause cardiac arrhythmias. 150-200 mg per day in 2-3 divided doses. Maximum dose 600 mg per day.

Side effects include increased serum digoxin and phenytoin levels, Sedation, drowsiness, dry mouth, Postural hypo tension, nausea, anorexia. MAOIs should not be given within one week of discontinuing the drug.

Other antidepressants

Amoxapine

It primarily inhibits NA reuptake of CNS neurons and also blocks dopamine D2 receptors. Dose 50 mg 2-3 times a day increasing gradually to 300 mg a day. It is mainly indicated in Psychotic depression.

TINAPETENE

It has effect on the storage and release of serotonin and mayfacilitate 5HT reuptake. It is indicated in endogenous, neurotic and reactive depression. Dose one tablet (12.5 mg) three times a day to be taken at the beginning of main meals. Side effects include drowsiness, dry mouth anorexia, nausea, vomiting, vertigo, hot flushes, and tremors.

VENLAFAXINE

It is a potent inhibitor of 5- NT uptake and weak inhibitor of NA transport. It behaves like an SSR at therapeutic doses. Indicated in major depression. Dose 75 mg per day in two or three divided doses. Side effects include Nausea, headache, dizziness, sweating, insomnia and asthma like features.

Drugs and depression

Of the various anti depressant medication, their use is to be made depending on the patients illness and experiences of the treating physician. Earlier on ECT (Electro convulsive therapy) was employed in patients who had dangerous suicidal tendencies and those in depressive stupor but now its use is limited. Depressive illnesses are best managed by psychotherapy and cognitive behaviour therapy (CBT) coupled with anti depressant medication.

Prophylaxis of Bipolar affective disorder (BPAD)

If there have been two or more episodes of mania or depression over two years, use of LITHIUM as a prophylactic agent may be considered.

The drug is neither sedative nor euphorient but on prolonged administration it acts as a mood stabilizer. Continued treatment prevents cyclic mood changes and attacks of depression. Dose 600 mg per day and gradually increased to yield therapeutic plasma levels of 900-1800 per day.

The drug has a narrow therapeutic window so it is important to monitor serum levels. Renal, thyroid functions and fluid and electrolyte balance be monitored.

Side-effects include nausea, vomiting, tremors, weight gain, thirst and polyuria. Cardiac arrhythmias can also occur. If symptoms of toxicity occur, lithium should be stopped and blood lithium levels assessed. (Normal blood level of lithium is 0.4-0.8 mmol/L. The levels at which toxicity occurs is variable in different individuals.

If lithium level is 1-5 mmol/L or more, the drug must be stopped and tailed off to precipitate a relapse. Drugs like diuretics, NSAIDs and ACE increase serum lithium levels while anti depressants and anti epileptics increase the risk of CNS toxicity.

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