Table of Contents

The Amine Theory of Depression

It is believed that depression is related to reduced levels of biogenic amines: Noradrenaline, 5-hydroxytryptarnine (5-HT or serotonin) and dopamine. Another possibility is that depression is associated with altered receptor sensitivity.

To understand the mechanism of action of antidepressants we need to look at neuronal transmission in the central nervous system. A presynaptic neurone stores the neurotransmitters in vesicles from which noradrenaline and 5HT are released.

The post-synaptic neurone has receptors for these neurotransmitters.  Some antidepressants block the re-uptake of noradrenaline and 5HT in the synaptic cleft.  Antidepressants vary in their effects, some act on noradrenaline transmission and others predominantly affect 5HT transmission and still others involve both.  The antideprresants increase the concentration of the neurotransmitters at the receptor site and hence neurotransmission is facilitated. 

Clomipramine and fluvoxamine are 5HT re-uptake inhibitors.

Monoamine oxidase inhibitors prevent the breakdown of noradrenaline and 5HT.  After treatment with such a drug there is an abundance of noradrenaline and 5HT in the synaptic cleft.  If a stimulant antidepressant is then given immediately such as clomipramine (Anafranil) because this blocks the re-uptake of noradrenaline and 5HT, a severe adrenergic reaction can occur and fatalities have been described.  The usual advice is not to give a tricyclic antidepressant within 15 days of the administration of a Monoamine oxidase inhibitors (MAOI).  There are however, safe combinations and it is best if both MAOI and certain tricyclics are started simultaneously in low dosage.  It is also unsafe to change from tranylcypromine (MAOI) to another MAOI without an interval. Both Noradrenaline reuptake inhibitors, and serotonin reuptake inhibitors are effective antidepressants and there is little difference clinically.  The amine hypothesis does not help in the choice of an appropriate antidepressant.

The First Generation Antidepressants

Imipramine (Tofranil) was discovered by chance in 1959.  This first tricyclic was closely followed by the introduction of the monoamine oxidase inhibitors. The tricyclic and MAOI antidepressants constitute the first generation antidepressants.

The Tricyclic Antidepressants:

Amitriptyline (Tryptizol) which is more sedative than imipramine was introduced in 1961; while two years later desipramine (Pertofran) which has more stimulant properties, became available. Trimipramine (Surmontil) which was introduced in 1964 is an excellent antidepressant which like amitriptyline is highly sedative and can often be given in one dose at night. Weight gain  however, can be a problem with tricyclics.

Dothiepin (Prothiaden) became the most widely prescribed antidepressant in Britain in 1984, 15 years after its introduction  It is an excellent drug, not because of greater therapeutic potency than the others, but its relative lack of side-effects.

^APPROVED NAME ^PROPRIETARY NAME ^YEAR OF INTRODUCTION^ |First Generation ||| |Imipramine |Tofranil|1959| |Monoamineoxidase inhibitors| (MAOI)|1959-1960| |Amitriptyline |Tryptizol|1961| |Desipramine|Pertofran|1963| |Nortriptyline|Allegron, Aventyl|1963| |Protriptyline|Concordin|1966| |Trimipramine|Surmontil|1966| |Iprindole|Prondol|1967| |Dothiepin|Prothiaden|1969| |Doxepin|Sinequan|1969| |Clomipramine|Anafranil|1970| |Second Generation ||| |Viloxazine|Vivalan|1974| |Maprotiline|Ludiomil|1975| |Butriptyline|Evadyne|1975| |Mianserin|Bolvidon, Norval|1976| |Trazodone|Molipaxin|1980| |Lofepramine|Gamanil|1983| |5HT reuptake inhibitors or selective serotonin reuptake inhibitors (SSRIs)||| |Fluvoxamine|Faverin|1987| |Fluoxetine|Prozac|1989| |Paroxetine|Seroxat|1991| |Sertraline|Lustral|1991| |Moclobemide|Manerix|1993|

Doxepin (Sinequan) was introduced in 1969; it has sedative properties and less cardio-toxic effects than amitriptyline. In 1970, clomipramine (Anafranil) came on the market. It was considered the best drug for obsessional neurosis, as it produces very good results in phobic anxiety states and panic disorders, although now SSRIs are used in these conditions. Problems of the Tricyclics

The problem with the tricyclics is their effect on the cardiovascular system.  They produce tachycardia, hypotension, they can produce abnormalities of the ECG, arrhythmias, bundle branch block and very rarely congestive cardiac failure. The autonomic side-effects include a dry mouth; constipation; micturition disturbances; blurred vision and sweating. There is a delayed onset of action but second generation antidepressants are claimed to have a more rapid onset of action. Other adverse effects include toxicity if taken as an overdose, which can lead to convulsions and death. They are slowly eliminated from the body and cannot be removed by dialysis.

The Monoamine Oxidase Inhibitors  (MAOIs)

These antidepressants were used extensively in the past, but have been superseded by newer antidepressants. The following is a list of MAOIs in an approximate order of potency.

|Iproniazid(Marsilid)| |Tranylcypromine (Parnate): [Parstelin has 1 mg of Trifluoperazine]| |Phenelzine(Nardil)| |Isocarboxazid(Marplan)|

Iproniazid was seldom used because of the increased risk of hepatotoxicity. Tranylcypromine is the most likely to cause a 'cheese reaction and isocarboxazid the least.

The use of combined antidepressants is complicated and should be restricted to those who are familiar with it. The treatment of a hypertensive 'cheese reaction' is to give the alpha adrenergic blocker, phentolamine (Regitine) 5 mg intravenously or chlorpromazine (Largactil) intramuscularly or orally. The risk of a hypertensive cheese reaction with tranylcypromine is five times that with phenelzine. The MAOIs are psychic energisers and should be given in the morning and at lunch time or they will keep the patient awake at night. 

Indications for MAOIs

Monoamine oxidase inhibitors are rarely used now. In the past they were used in patients who have failed to respond to other antidepressants. Anxious patients with panic attacks and depression used to respond well to these antidepressants. L-tryptophan (Optimax, Pacitron) is the precursor of 5HT (serotonin) and is not a first rank antidepressant.  It causes sedation and has been used in combination with an MAOI to increase its potency. When this is done, there may also be an increase in the side-effects of  the MAOI and there is now the recommendation (BNF) that this combination is not safe.

The Second Generation Antidepressants

It has been estimated that by 1983, there were 81 new antidepressants being developed in Europe.

Viloxazine (Vivalan), a bicyclic can be considered the first of the second generation antidepressants.  It has anticonvulsant properties but the side-effects include nausea, loss of appetite and occasionally vomiting.  It can be used for patients with epilepsy but its antidepressant properties are very weak.

Maprotiline (Ludiomil) was the first of the tetracyclics to be introduced in 1975. It inhibits noradrenaline, is highly sedative and an effective antidepressant, but appears to have no advantages over the tricyclics. It can have marked cardiotoxic effects if an overdose is taken, and lowers the epilepsy threshold.

Mianserin (Bolvidon, Norval) which was introduced in 1976, is a very effective tetracyclic.  It is suggested that 10 mg of mianserin is equivalent to 25 mg of imipramine.  It was discovered because it produces the same EEG changes as first generation antidepressants.  It has much less effect on the cardiovascular system, produces few anticholinergic side-effects, but its biggest problem is weight gain. 

There is the possibility of it producing bone marrow depression which usually present with neutropenia within the first six weeks of administration.  This is generally reversible on stopping treatment but if a patient develops symptoms of infection for example fever, sore throat or stomatitis during treatment, the medication should be stopped and a full blood count obtained.

Trazodone (Molipaxin) is a very selective inhibitor of 5HT and is claimed to have a rapid onset of action.  It is sedative and has been used for decades in the USA as Desyrel. A considerable advantage is that it is does not cause seizures, it does not inhibit MAO, and interactions between it and MAOIs have not been reported. Weight loss can be a side-effect, it may slow the heart rate, arrhythmias have been reported, but it does not have anti-cholinergic side-effects. A rare complication is priapism severe enough to need surgical treatment in young men.

Another tricyclic was introduced in 1983, Lofepramine (Gamanil), which does not have the anticholinergic side-effects of other tricyclics and is less sedative than amitriptyline.  There is no evidence of cardiotoxicity at therapeutic doses. It is said to have a rapid onset of action, and to be anxiolytic and has not resulted in death, even following a massive overdose.

Serotonin Re-uptake Inhibitors:

Fluvoxamine (Faverin) was introduced into the UK in 1987.  It is a highly selective 5HT re-uptake inhibitor.  It is different from tricyclics in that it does not produce typical anti-cholinergic side-effects such as a dry mouth, sweating or postural hypotension, and has minimal cardiotropic action.  Nausea can be a problem but weight gain does not occur.  It is neither especially sedative nor stimulant.  One dose at night is probably best, up to 150 mg; thereafter 50 mg or more can be added in the morning.  It is useful in obsessional neurosis and panic disorder.

Fluoxetine (Prozac) was introduced into the UK in 1989.  It is also a -highly selective 5HT re-uptake inhibitor. The starting dose is 20 mg. it can be increased to 60 mg.  It has been used for depression, obsessional neurosis, panic disorder and eating disorders.  Both fluoxetine and fluvoxamine are much safer than tricyclics if taken as an overdose. Fluoxetine (Prozac)  can be very stimulant and make people more panicky initially. It has a very long ½ life.  MAOIs should not be used for 5 weeks after discontinuation of Fluoxetine.

Paroxetine (Seroxat) is another 5HT re-uptake inhibitor.  The starting dose is 10 mg, increasing after a few days to 20 mg with breakfast. Although given in the morning it can help insomnia.  Gastro­intestinal side-effects are similar to sertraline. The dose can be increased up to 40 mg-50mg. It is advised to wait two weeks before giving MAOIs.  Sexual dysfunction can occur and severe withdrawal symptoms are reported on discontinuation of paroxetine.

Sertraline (Lustral) is also a 5HT re-uptake inhibitor.  It has a long half-life (26 hours) and similarly given once daily in doses of 50-200 mg.  It may cause nausea and insomnia. It has a very different formula from the other 5HT reuptake inhibitors such as fluvoxamine, fluoxetine and paroxetine. There is some evidence that it can prevent depressive relapses.

Unwanted Effects of SSRIs

Adverse reactions, including convulsions and hyperpyrexia, have been reported after simultaneous administration of an SSRI and lithium (Committee of Safety of Medicines, 1989).  Insomnia occurs in 15% of patients taking fluoxetine, paroxetine or sertaline and 5% of those taking fluvoxamine. Withdrawal symptoms (dizziness, sweating and tremor) occur if paroxetine is stopped abruptly.

Sexual dysfunction (e.g. delayed ejaculation) affects about 17% of patients receiving sertraline and 3% of those on paroxetine. A rare but fatal systemic vasculitis with fluoxetine has been described, as has serum sickness. Amoxapine (Asendis) was also introduced to the UK in 1989.  It is a dibenzoxepine, distinct from the dibenzepines such as imipramine.  Its primary action is to block noradrenaline re-uptake. and its secondary action, the blockade of serotonin uptake.  It is said to act more rapidly than tricyclic antidepressants. Amoxapine may cause movement disorders (dose range 100-300 mg per day)

DUAL ACTION SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS:

Nefazodone (Dutonin), the first dual action SSRI was introduced into the UK in 1995. Structurally, it is a derivative of trazodone, which itself is an antidepressant drug related to the Tricyclic Antidepressants. It exhibits a dual action on both the neurotransmitter serotonin and its receptors. Nefazodone inhibits the re-uptake of serotonin into the presynaptic neurone and selectively blocks postsynaptic 5-HT2 receptors.

Nefazodone is used in the treatment of depressive disorders in a dosage of 50 mg twice daily for one week, then 100 mg twice daily for one week, then stepping it up to the usual therapeutic dose of 200 mg twice daily.

Adverse effects is less difficult to tolerate. It causes less gastrointestinal side effects and less sexual dysfunction than other selective serotonin Reuptake inhibitors(SSRIs). The frequently reported side-effects are visual disturbances (including amblyopia, i.e. visual impairment without apparent organic pathology) and light-headedness. The drug promotes sleep due to the blockade of 5-HT receptors.

It requires twice daily dosing, compared to the once daily dosing with SSRIs. This may reduce compliance in patients taking nefazodone for the long-term treatment of depression, as compared to patients taking SSRIs.

SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS (SNRIs)

Venlafaxine (the first SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS) was introduced into the UK in 1995. It is structurally a bicyclic antidepressant. It selectively inhibits the re-uptake of both serotonin and noradrenaline into the presynaptic neurone.

Venlafaxine is used for the treatment of depressive disorders in a dosage of 37.5 mg. twice daily; this may be increased to 75 mg twice daily in mild to moderate depression; then it may be further increased by 75 mg increments every 2-3 days to a maximum of 375 mg daily (preferably in hospitalized severe depression). There is some evidence that venlafxine is effective in treatment of resistant depression.

Adverse effects:

Compared to Tricyclic antidepressants, venlafaxine caused less anticholinergic side-effects and less clinically significant cardiovascular side-effects. It is thus safer in overdosage as compared to tricyclic antidepressants and less likely to cause weight gain. Gastrointestinal side-effects (for example nausea) are dose related and occur with a similar prevalence to those observed with SSRIs. In hypertension, blood pressure should be monitored in patients taking 225 mg daily or more. It is reported that Venlafaxine may precipitate hypomania in patients with bipolar affective disorder. The most frequently reported side-effects are sweating and headache. It requires twice daily dosing. A once-a-day formulation of venlafaxine (XL or MR, modified release) was launched in the UK in 1997 (dosage: 75 mg daily; if further clinical improvement is required, this may be increased to 150 mg daily; it may be further increased to a maximum of 225mg daily if required). This may help compliance in patients taking venlafaxine for the long-term treatment of depression.

Other Substances:

Flupenthixol (Fluanxol) has been shown to have antidepressant properties in controlled trials. It is a neuroleptic of the thioxanthene series,  and does not produce photosensitivity or anticholinergic side-effects. It is relatively safe in. There is the suggestion that the benzodiazepine alprazolam (Xanax) has antidepressant properties and it was released in the USA in 1981 for the treatment of mild to moderate depression.

There is increasing evidence to show that lithium enhances the effect of antidepressants and can produce a rapid rise in 5HT. Previously unresponsive patients have shown clinical improvement within 24-48 hours of using lithium therapy with antidepressants.

Moclobemide (Manerix)

Moclebemide is the first reversible inhibitor of monoamine oxidase type A (RIMA). It causes less potentiation of tyramine than traditional irreversible MAOIs and therefore does not generally necessitate the special MAOI diet.  It has a very short ½ life, measured in hours not days.  No washout period is required following dis­continuation of therapy.   It is effective in all forms of depression.

It should not be combined with 5-HT re-uptake  inhibitors (especially clomipramine) or buspirone. It potentiates ibuprofen (Brufen) and opiates. Patients should avoid pethidine, codeine, ephedrine, pseudoephedrine and phenylpropanolamine (contained in many cold-cures). Concomitant cimetidine (Tagamet) treatment requires initiation with half the dose of moclobemide. There is no problem in combining moclobemide with lithium. No reports of death when moclobemide was taken as the sole drug in overdose. Usual dose 150 mg or 300 mg with breakfast and lunch.  Maximum dose 600 mg a day.  The commonest side effects are insomnia and dizziness.

GUIDELINES FOR THE TREATMENT OF DIFFERENT CLINICAL SYNDROMES

^Clinical Syndrome^Antidepressants| |Epilepsy |Imipramine (Tofranil), Doxepin (Sinequan), Isocarboxazid (Marplan)| |No seizures.|Viloxazine (Vivalan)| |Cardiac patient|Paroxetine (Seroxat), Fluoxetine (Prozac), Sertraline (Lustral)|

Fluvoxamine (Faverin) slows the heart slightly and has no interaction with digoxin or atenolol, but care should be taken with patients already on propranolol and warfarin, as the dose of these drugs may need to be lowered. Alternatives, mianserin (Bolvidon, Norval) if sedation is required, or lofepramine (Gamanil) Hypertension

SSRIS are best, as unlike tricyclics there is little interaction with anti-hypertensive drugs such as guanethidine.

Beta-adrenergic blockers plus tricyclic is a useful combination.

Watch for depression caused by alpha-methyldopa and reserpine.

Parkinson's Disease

Trazodone (Molipaxin) Elderly Moclobemide (Manerix). Tricyclics in smaller doses, increased more gradually. MAOIs have fewer anticholinergic and cardiotoxic effects than tricyclics.

Glaucoma and Prostatic enlargement

Trazodone (Molipaxin) reputed to lower intra-ocular tension (priapism is a rare serious side-effect).

Pregnancy

Avoid antidepressants if possible during first trimester. There is no evidence of foetal abnormalities with tricyclics.

Premenstrual tension

Oil of evening primrose, Efamol (gamma­linolenic acid) may help. Its available from health food shops without prescrip­tion. Vitamin B6-pyridoxine (Benadon). Contra-indicated if the patient is on levodopa

Obsessional neurosis

Clomipramine (Anafranil), much the best. Fluvoxamine (Faverin), Fluoxetine (Prozac), Paroxetine (Seroxat) and Sertraline (Lustral) second best.

Alcoholism

Antidepressants and tranquillisers will not benefit the patient until he or she has stopped drinking. It is like painting over rust. They are usually unnecessary in the abstinent. Paroxetine (Seroxat) and Sertraline (Lustral) and Moclobemide (Manerix) do not enhance effects of alcohol. Concomitant use not advised.

Patients who drive

Tricyclics at night only, e.g. less-sedative Dothiepin (Prothiaden) best, or MAOI during the day (psychic energiser).

Suicidal patients

Only 4% of suicides are due to anti­depressant overdose. SSRIs and Moclobemide are much safer if taken as an overdose but they can cause agitation before depression is lifted. Lofepramine (Gamanil) is also less cardiotoxic.

Enuresis, School phobias, Premature ejaculation

Imipramine (Tofranil) or other tricyclics.

Chronic pain

Amitriptyline (Tryptizol) and trimipramine (Surmontil) may help.They will improve sleep.

Obese

MAOIs and lithium can also cause weight gain.

Types of antidepressants

A) Tricyclic antidepressants (TCAs) 1. Tertiary amine tricyclic antidepressants: Amitriptyline (Elavil, Endep) Clomipramine (Anafranil) Doxepin (Adapin, Sinequan) Imipramine (Tofranil) Trimipramine (Surmontil) 2. Secondary amine tricyclic antidepressants Desipramine (Norpramin) Nortriptyline (Pamelor, Aventyl, Noritren) Protriptyline (Vivactil) Monoamine oxidase inhibitor (MAOIs) Isocarboxazid (Marplan) Moclobemide (Manerix) Phenelzine (Nardil) Selegiline (Emsam) Tranylcypromine (Parnate) B) Selective serotonin reuptake inhibitors (SSRIs) Citalopram (Celexa, Cipramil) Escitalopram (Lexapro, Cipralex, Seroplex, Lexamil) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil, Seroxat) Sertraline (Lustral, Zoloft) C) Serotonin-norepinephrine reuptake inhibitors (SNRIs) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Ixel) Venlafaxine (Effexor) D) Noradrenergic and specific serotonergic antidepressants (NaSSAs) Mianserin (Tolvon) Mirtazapine (Remeron, Avanza, Zispin) Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) Atomoxetine (Strattera) Mazindol (Mazanor, Sanorex) Reboxetine (Edronax) Viloxazine (Vivalan) E) Norepinephrine-dopamine reuptake inhibitors (NDRIs) Bupropion (Wellbutrin, Zyban)

Augmentation of action of antidepressants

A number of patients do not respond to trial of one antidepressant after another even when adequate doses are used and giving treatment enough time to work. When two antidepressants have been tried without success, a number of strategies are applied to achieve recovery.

Strategies in augmentation of Antidepressant therapy

  • Using another antidepressant from a different group, such as SSRI or mirtazapine, moclobemide, reboxetine and tricyclic antidepressants.
  • Add atypical antipsychotic to SSRI.
  • Add noradrengic reuptake inhibitor such as reboxetine to SSRI.
  • Add Lithium to the antidepressant.
  • Add mianserin or mirtazapine to SSRI.
  • Add Phenelzine or another MAOIs
  • Add anticonvulsant such as carbamazepine, sodium valproate or lamotrigine.
  • Add Tri-iodothyronine (T3) to the antidepressant.
  • Add pindolol, or buspirone.

If patients fail to respond to antidepressant treatment, review the psychological factors, which may be pertinent :The marriage, the job, the social situation. When re-evaluating the medication and drug history, ensure that an adequate dosage has been given; that the medication was taken for long enough to produce benefit and that the patient has persisted with the medication and has not defaulted.   Delayed recovery may be due to alcohol,  street drugs or other drugs.  It is a cardinal error to withdraw an antidepressant too soon after recovery.  This will invite relapse.  It should be continued for 3-6 months for prophylaxis and then reduced gradually.

Whatever medication is prescribed, it is vital that this is combined with the therapeutic virtues of empathy, genuineness and warmth.  Use of a combination of antidepressant and psychotherapy, in particular cognitive behaviour therapy give a better recovery in depression.

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