Addiction Treatment Blog

There are seven major physical treatments for depression at present.

• Tricyclic Antidepressants (Table 1). These have until recently been by far the most widely used.
• The Monoamine Oxidase Inhibitors (MAOIs) (Table 2).
• Reversible Inhibitors of Monoamine Oxidase (RIMAs) (Table 3).
• 5-HT Reuptake Inhibitors (Table 4).
• Other Antidepressants (Table 5).
• Treatments for Bipolar Disorders or Prophylaxis of Recurrent Disorders (Table 6).
• Others (Table 7)

In the last category, a number of other treatments are marketed for or used for depression and they often work, but whether they are antidepressants in the same sense as electroconvulsive therapy (ECT), imipramine or phenelzine is a matter of dispute. The 5-HT-1a agonist, buspirone, has in addition been marketed as an antidepressant, and a further compound from this group, flesinoxan, looks as though it may also emerge as an antidepressant.

Finally, there is also ECT, the mechanism of action of which, and its use clinically will not be discussed at any length in this article. Its role when antidepressants fail to work and in cases of mania will be considered at a later stage.

Table 1: Tricyclic antidepressants
Drug name	UK Trade Name	US Trade Name
amitriptyline	Tryptizol/Lentizol	Elavil/Endep
imipramine	Tofranil	Tofranil
nortriptyline	Allegron (Motival/Motipress)	Aventyl
protriptyline	Concordin	Vivactil
desipramine	Pertofran	Pertofrane
norpramin	Norpramin	Norpramin
clomipramine	Anafranil	Anafranil
dothiepin	Prothiaden	n/a
lofepramine	Gamanil	n/a
doxepin	Sinequan	Adapin/Sinequan
trimipramine	Surmonil	Surmontil

Table 2: The monoamine oxidase inhibitors
Drug name	UK Trade Name	US Trade Name
phenelzine	Nardil	Nardil
tranylcypromine	Parnate also in Parstelin	Parnate

Antidepressants are different

Until the advent of Prozac, many people hadn’t heard about the antidepressants. They were the poor cousins of both the major and minor tranquillisers. Even now there can be difficulties persuading someone to have an antidepressant owing to a perception that, despite what they are being told, these drugs must be tranquillisers in some sense. In many respects, however, the antidepressants are perhaps the most unusual psychiatric drugs.

There are four important ways in which they differ from other drugs.

Unlike any other drugs that act on the brain, whether tea or coffee, nicotine or alcohol, neuroleptics, minor tranquillisers, marijuana or other illegal drugs, the antidepressants do within 30 mins is to produce side effects. The lifting of a depressed mood, in contrast, typically takes up to 2 weeks and sometimes longer to begin to appear. Because other drugs, such as tea or tranquillisers act within 30 mins and their effects wear off in a few hours, it is usual to take them several times every day – a cup of coffee every few hours for example. Antidepressants are different. It seems sufficient to take them once a day. For this reason they are now given in one dose last thing at night or first thing in the morning. There are even some indications that antidepressants would work as well if given in a large dose every 2 or 3 days rather than each day. One of the physical treatments for depression – ECT – is given in just this way, every few days.

Another unusual feature of antidepressants is that they only seem to do anything to people who are depressed. This is not true for tea, coffee, neuroleptics or any of the other drugs, such as diazepam for example, which have much the same action on people who are unaffected by mental illness, or who have schizophrenia, depression, mania, anxiety or any other nervous disorder. In contrast, antidepressants only seem to ‘antidepress‘ people who are depressed in the first place. They do not make people who are not depressed, feel calmer, more tranquil, happier or elated in any way. In some cases they may not do anything at all, even for someone who is depressed. This is quite different from cocaine, amphetamines or other stimulants which act in the short term to give a euphoric boost to everyone, whether they are clinically depressed in the first place or not. Antidepressants are not stimulants. Both mental health workers and people who take these drugs sometimes think that antidepressants are a legal version of cocaine. This is not the case.

A further unusual feature of the antidepressants, when compared to other psychotropic drugs, is that broadly speaking it is not the case that some of an antidepressant does a little bit of good and more of it does more good, as it is with tea or coffee. With coffee, one cup may be alerting, two cups more alerting and three cups get you really wired up. But with antidepressants it seems to be that if one takes a dose below a certain threshold nothing at all happens, apart from side effects. Furthermore doses greatly in excess of the threshold do not seem to operate any more effectively, or any more quickly than the threshold dose. Indeed, all they are simply likely to cause are further side effects.

Finally, antidepressants differ from the other drugs in psychiatric use in that in overdose, most antidepressants can be fatal in relatively small amounts, although this is much less the case with some of the more recently produced compounds.

Table 3: Reversible inhibitors of monoamine oxidase
Drug name	UK Trade Name	US Trade Name
moclobemide	Mannerix	n/a

Table 4: 5-HT reuptake inhibitors
Drug name	UK Trade Name	US Trade Name
citalopram	Cipramil	n/a
fluvoxamine	Faverin	Luvox
fluoxetine	Prozac	Prozac
paroxetine	Seroxat	Paxil
sertraline	Lustral	Zoloft
venlafaxine	Efexor	Effexor

Table 5: Other antidepressants
Drug name	UK Trade Name	US Trade Name
mianserin	Norval/Bolvidon/Tolvon	n/a
mirtazepine	Zispin	Remeron
trazodone	Molipaxin	Desyrel
nefazodone	Dutonin	Serzeno
maprotiline	Ludiomil	Ludiomil
viloxazine	Vivalan	n/a
buproprion	n/a	Wellbutrin
L-tryptophan	Optimax	Trofan

Table 6: Drugs used in the treatment of prophylaxis of bipolar disorders
Drug name	UK Trade Name	US Trade Name
lithium carbonate	Camcolit/Priadel	Eskalith/Lithobid
lithium citrate	Li-Liquid/Litarex
carbamazepine	Tegretol	Tegretol
sodium valbroate/valproic acid acetazolamide	Epilim	Depakote

Table 7: Other classes of drugs used as antidepressants
Benzodiazepines
chlordiazepoxide	diazepam	alprazolam
neuroleptics
flupenthixol	thioridazine

Antidepressants and Depression

When we say antidepressants treat depression, what do we mean? As outlined in the introduction this is hard to specify. Consider the discovery of antidepressants. In the case of drugs such as the neuroleptics or benzodiazepines, discovery was uncomplicated since these drugs bring about clear changes a few minutes after taking them, noticeable to both the taker and others. From what we know of antidepressants, it is clear that even if these drugs has been given to everyone, for extended periods of time, nothing might ever have been discovered. Discovery only happened when these drugs had been given to everyone, for extended periods of time, nothing might ever have been discovered. Discovery only happened when these drugs were given to a particular group of patients – and even then it took several weeks of treatment before they made sad people happy. Both an illness and the pills had to be discovered at the same time.

The illness has been called vital, biological or endogenous depression. This state corresponds to what in previous centuries was sometimes called melancholia (this term seems to be coming back into fashion once again). This is a state characterised by the following:

• Loss of energy.
• Loss of interest.
• Feeling physically ill/below par/run down.
• Poor concentration.
• Altered appetite.
• Altered sleep.
• A slowing of physical and mental functions.

These are the core symptoms, which are predominantly physical in character. For most people who get the disorder, it is rather like having a mild influenza. For some it is more severe.

In addition to the core symptoms, there are a number of other physical problems that may come along with a depression. These include:

• Heartburn.
• Indigestion.
• Constipation.
• Ulcers of the gut.
• Dry skin, hair and mouth.
• Pins and needles.
• Odd pains around the body.
• Headaches.
• Altered periods.

In addition to these physical symptoms, there is also sadness, hopelessness, guilt and suicidal ideas. However, going through this checklist of symptoms should bring home the point that the condition which antidepressants treat is not ordinary sadness, guilt or hopelessness. Nor do they treat severe hopelessness, guilt or sadness. What they treat is something different from what most people think of as depression. Indeed, the term depression was only introduced for this condition in the early years of the last century.

In all cases for which antidepressants are helpful there will be some of the above physical symptoms. But in most of these cases there will also be some of the following psychological symptoms:

• Hopelessness.
• Helplessness.
• Guilt.
• Ruminations.
• Anxiety.
• Suicidal ideas, or a wish to be dead.

Anti depressants will commonly be of little use for individuals who have these psychological symptoms but not any of the preceding physical symptoms. They are not anti-psychological-problem pills, although this issue is clouded somewhat by their increased use in number of anxiety states.

In some cases, people who are depressed become so anxious, or suicidal, or guilty that the most obvious thing about them is that they are anxious or suicidal rather than that they are suffering from a mild physical illness. On the surface, they may only appear to be anxious or suicidal without having the physical disturbances we have mentioned, but if they have an underlying depression, their anxiety will get better on antidepressants.

Reactive and Endogenous Depression

It is commonly thought that the kind of depression that comes on after a life event is a mild psychological problem that should not be treated with antidepressants, in contrast to endogenous depression. This is more severe biological illness that is not triggered by life events, and which may be appropriately treated with pills.

These ideas are largely a consequence of the development of ECT and antidepressants. Before these treatments, it was much less common to make distinctions between depressions. With ECT and the tricyclic antidepressants, it appeared that the more severe depressions, and in particular those with clear physical features, responded to treatment, whereas the response of states of anxious misery or morbid distress was much less convincing.

The former became known as the endogenous depressions. They were presumed to arise from some biochemical change in the brain, a reasonable view given the efficacy of chemicals in putting these conditions right. The latter were the reactive or neurotic depressions. These were presumed to arise in response to life crises and accordingly many have assumed that treatment with antidepressants must be inappropriate in these milder depressions.

Current research suggests that these views are wrong. Depressions with physical features, the so-called endogenous depressions, are known to be triggered by life events just as often as neurotic depressions. Antidepressants are helpful for many seemingly mild depressions – provided the condition is not just one of misery. In current psychiatric practice the terms endogenous and depressive disorder, which is responsive to antidepressants and minor depressive disorder or dysthymia, which is much less likely to respond convincingly.

Recent Developments

Since 1980, there has been increasing recognition of post-traumatic stress disorders, of which the grief reaction to the loss of a loved-one is the most common. Others include the shocks that may be consequent on traffic accidents, rape, public disasters, etc. These states will be considered further at a later stage. Their relevance here is that although they are primarily anxiety disorders, they may involve serious mood changes, leading to an abrupt descent into severe depressions. Typically these mood changes are briefer than major depressive disorder and do not have the same physical character.

Psychiatrically, the post-traumatic stress disorders are most likely to cause a problem when the trauma has occurred in childhood and has given rise to what is termed a borderline personality organisation. This state often leads to repeated suicidal acts, or self-injurious behaviour and states of profound desperation. For the most part, antidepressants are not helpful in these disorders and may indeed even make the condition worse. This issue is complex in that someone who is grieving or traumatised may later go on to become depressed in a way that will respond to antidepressants.

Another set of developments has been the demonstration that a number of brief focused psychotherapies – in particular interpersonal therapy (IPT) and cognitive therapy (CT) can bring about a clear response in depressions that would also be expected to respond to antidepressants. The fact that the same depressions respond to a number of very different types of interventions suggests that there is not just one right way to treat a depression. It might be better, therefore, to regard the different treatments as offering antidepressant principles. There are considerable differences between the tricyclic, MAOI and SSRI (selective serotonin reuptake inhibitor) antidepressants, which suggest that they may also act according to quite different principles.

Finally, there is an increasing recognition that the depressions that ended up in hospital during the 1950s, 60s and 70s were in many respects atypical. This is of significance, as it was from amongst this subject group that the volunteers for clinical studies on the antidepressants were drawn. Today it is recognised that most depressions that could respond to antidepressants are being seen by general practitioners rather than psychiatrists – in a ratio of over 20 to 1. Studying this larger group has led to the conclusion that depression often resolves spontaneously over time, the average being somewhere around 14 weeks.

A model for depression and antidepressants

Ulcers and their treatment provide a helpful mode for the effects antidepressants have on depression. For example, if one considers the question that often seems to puzzle people – how can an illness come on after stress/life events – it is clear for ulcers that a very real physical illness can come on after stress. Ulcers are not just a psychological problem. And they do not necessarily clear up once the stress goes away or one learns to manage it. They also are appropriately treated by drugs.

Initially anti-ulcer drugs have little or no effect on an ulcer. The pain remains and there seems to be little improvement. If continued, however, after a week or two the pain of the ulcer begins to resolve as the wound closes over. As the pain clears up, the anxiety that goes with having an ulcer also goes.

The effects that antidepressants have on hopelessness, guilt and suicidal thoughts are similar to the effect and anti-ulcer pills have on anxiety. Once the core physical problems clear the associated psychological reactions also clear up. In the same way that no one would give anti-ulcer drugs to patients, who are anxious but who do not have an ulcer, so antidepressants are of little use in sadness and unhappiness if patients do not have the kind of brain ‘ulcer’ I am calling depression.

Considering depression in terms of a brain ulcer allows us to offer answers to questions such as how long should treatment continue, should drugs be combined with psychotherapy, and do antidepressants cure?

How long should treatment continue?

Current research suggests that it is prudent to stay on an antidepressant for at least 3 and probably 6 months after starting to feel well. This is much the same advice that is given to patients who have ulcers, who are recommended to stay on their treatment for 3-6 months after the ulcer has closed. This seems to be because the period when ulcers are most likely to reopen seems to be during the 3-6 month period after initial recovery.

This does not mean that halting antidepressants immediately after recovery would necessarily lead to relapse. In many cases stopping can be done successfully. However, the risks of relapse are far less if one is prepared to go on with the antidepressant for 3-6 months afterwards. The risks of relapse seem to increase according to the number of previous episodes an individual has had and the severity of those episodes. If there have been a number of clear-cut previous episodes, severe enough to warrant hospitalisation, current opinion would lean toward possibly permanent ongoing treatment. In the case of ulcers, frequent relapse seems to be associated with the presence of an organism called Helicobacter pylori and quite different treatment of the usual anti-ulcer treatment is called for. Whether something comparable applies in depression is at present unclear.

Drugs and/or psychotherapy?

The ulcer model brings out one further aspect of the use of antidepressants. Provided they are not too severe, it is often possible to treat ulcers without recourse to physical treatments at all. By eating a lot of small, bland meals throughout the day rather than large, hot and spicy meals, along with avoiding smoking and alcohol as well as relaxing, one can often cure an ulcer without any drugs at all. This seems to be because ulcers, just like wounds on the hand, heal naturally unless there is something interfering with the healing. Exactly the same thing seems to be true for ‘biological’ depressions. Even though they are a physical disorder, it now seems that in many cases they can be treated without pills, by a number of newly developed therapies of which cognitive and interpersonal therapy are the best known.

Regarding the treatment of depression without pills, two points can be made. One is that it is not always the case that ulcers can be treated without pills. If the ulcer is located on the posterior wall of the gut or if the individual has higher than average gastric acid levels or an infection with Helicobacter pylori, the ulcer is liable to be somewhat slower to heal or more likely to reopen. Chronic ongoing stress also interferes with spontaneous recovery. In many cases treatment with anti-ulcer drugs is necessary. Indeed it may even be necessary to proceed to surgical intervention.

Much the same seems to be true of depression. Recent evidence suggests that the majority of depressive disorders that could responds to antidepressants clear up themselves, eventually. Most of them seem to last for anything between 1 week to 3 months. Some however can last for longer than this, sometimes over a year, and a small proportion of these may become relatively permanent states of depression, or involve a constant cycling between depression and elation.

Secondly, in the case of ulcers, relaxing and taking bland meals as well as taking an anti-ulcer pill is the quickest and most certain way to treat your ulcer. In the same way, combining antidepressants and the latest techniques to handle depression psychologically is probably quicker and more likely to lead to cure than only taking antidepressants, or having cognitive therapy without pills for example. There are strong suggestions that the combination of treatments is likely to be the most effective means of preventing any relapse.

Do antidepressants cure?

Many people think that antidepressants and ECT don’t cure anything, that they only suppress problems, or blunt reactions to some trauma until the individual has a chance to recover. This view is arguably true of both the neuroleptics and minor tranquillisers, but less so of antidepressants. The effect of antidepressants on depression, in this regard, is like the effect of anti-ulcer pills on ulcers. Many people who are treated for an ulcer will only ever have that one ulcer. The pills cure it. In the same way with depression, many people only ever have one serious episode.

Another way of putting this question is does depression ever truly clear up? The answer is yes. However, just like ulcers and influenza, depression is a disorder which, even if this episode is cured, may recur. There are some suggestions that recurrence is more likely if the initial episode was inadequately treated. Current estimates are that perhaps up to half of us have at least one episode of biological depression during our life, although this may be so physical or so mild that it may not be clearly recognised as a ‘depression’.

While antidepressants do cure most depression, some people go on to have a chronic depression and others regular episodes of depression. Sometimes alternating with elation. It is probable that a variety of physical or psychological factors, such as mildly abnormal endocrine status pre-existing impairments of self-esteem, make this more likely.

Does psychotherapy cure better than antidepressants? The answer to this appears to be no. Even if a depression has been cured with the latest techniques, it may relapse in just the same way after psychotherapies. In this regard depression, just like ulcers, seems to be a physical illness that clears up but may also come back. It is not an illness like coronary artery disease or rheumatoid arthritis which, once you have it, can never really be cured.

Finally, antidepressants also resemble anti-ulcer pills in two other ways. One is that just as there are a number of quite different ways of treating an ulcer – a number of different therapeutic principles – so also are there a number of different antidepressant principles. The tricyclics are more like tonics in some respects, they improve sleep and appetite, the SSRIs are more anxiolytic and the MAOIs may be more energising than the others.

In addition while antidepressants and anti-ulcer treatments often cure the illness, for both treatment relapse is possible even when the patient is on active treatment.

What do antidepressants do?

For neuroleptics and benzodiazepines, compelling theories exist for how the drugs work. This is not the so with antidepressants.

The principal theories about what the antidepressants do to biological systems in the brain have focused on their effects on the neurotransmitters, noradrenaline and 5-HT (serotonin). The first of these theories, the catecholamine hypothesis of depression, was put forward in 1965. It was based on the idea that drugs, which lower noradrenaline or 5-HT in the brain seemed to trigger depression and the then known antidepressants appeared to increase the levels of these neurotransmitters. This hypothesis and its derivatives have dominated thinking on the mode of action of antidepressants and in particular are the theories that are put forward in popular books on depression or antidepressants by many of us or in articles from magazines such as Cosmopolitan or Esquire. The truth, however, is that despite over two decades of work there still is no convincing theory about what antidepressants do. To suggest that there is one would be misleading.

This lack of convincing rationale for what antidepressants do leads some people to have grave doubts about taking them. It should be borne in mind, however, that the questions of whether antidepressants work and how they work are two separate questions. For most drugs, we have no good idea how they work but convincing indications that they do. This situation comes about because most drugs are developed by chance rather than by rational design, although many psychiatrists, psychopharmacologists and drug companies would often have us believe otherwise. In the case of antidepressants, while we do not know what they do, there is compelling evidence that they work and a good case can be made that, in many cases, they cure.

Clinically, for the first 2 weeks of treatment, antidepressants usually do little except cause side effects. Even after that, unless the patient swings dramatically into a mildly manic state, they may not seem to do much.

The change brought about seems to creep up on people rather than sweeping on them. It seems to be like the kind of change that goes with a ‘flu, clearing up rather than the instant and dramatic changes brought about, for instance, by anti-anginal tablets for angina, or by bronchodilators for asthma. What happens usually is that there is a slow increase in energy, a slow return of interest, a mild increase in appetite and improvement in sleep. These occur gradually rather than clearly and they may be patchy, for example, with one good night’s sleep tonight followed by a poor one and then a good one the night after; like a change of season, to use the climate analogy again.

For the most part, improvements in the sadness, hopelessness, guilt and suicidal thoughts that may go with depression seem to occur as a reaction to changes in things like sleep, energy and interest. They often therefore take somewhat longer to become established. Sometimes, sleep improves and energy and interest increase, but the individual may remain demoralised. The temptation in such cases is to increase the dose of the antidepressant, but this rarely produces the hoped for benefits.

In general, antidepressants have little or no effect on individuals who are sad, guilty or anxious, but who have no underlying loss of energy, interest, poor concentration or a feeling of being physically off colour or out of tune. Giving them to people who are sad or anxious but not depressed may be a very bad idea, as they can be fatal should the taker decide to overdose.

Antidepressants: First choice or last resort?

Given that many depressions heal naturally and that psychotherapy can help, should one take antidepressants at all? Many argue that you should not. there are commonly three different objections put forward that we will consider. One is that antidepressants alter brain chemistry, and this cannot be a good idea. Another is that antidepressants block messages in the brain, and this cannot be a good idea. The third is that the use of antidepressants will interfere with the development of natural coping mechanisms.

Antidepressants and brain chemistry

Antidepressants do act on receptors in the brain. Not only this but they alter far more brain receptors than drugs like the tranquillisers, for example. Quite mysteriously, they even bring about changes in brain receptors on which the drugs themselves do not act. Could this predispose individuals who take these pills to further episodes of depression, by making them chemically unstable?

The answer to this is no. Unlike other drugs which act on the brain, antidepressants act ‘weakly’ on the brain receptors they bind to. They neither vigorously act on, or comprehensively block, anything. The changes they bring about tend to be within the range of changes that are happening during the day anyway – brain receptors and enzymes fluctuate in levels according to a circadian rhythm. This is quite different to the effects of coffee, tranquillisers or alcohol, for example, which push the brain systems they act on well beyond the normal range of circadian variation.

A further important point is that the illness itself also brings about changes in brain functioning. For example, it is known that depression causes an elevation of the stress hormone, cortisol. What has recently become clear is that prolonged elevations of cortisol reset the central mechanisms controlling cortisol levels to a higher setting. This in turn is liable to lead to an elevated cortisol level even when the person is not depressed. Elevations of cortisol may even in time lead to brain cell loss and premature ageing. Chronically raised cortisol levels will lead to far more comprehensive and long-lasting changes in brain receptors than antidepressants ever bring about.

Whether via cortisol or another mechanism, ongoing depression predisposes to future relapses of a depressive episode and to increasing severity of that episode. It is also likely to increase the risk for tumours and infections. Indeed, a dramatic discovery has been that the presence of depressive symptoms after a heart attack is a significant factor in determining recovery from the attack – the presence of depressive symptoms greatly increases the likelihood of death in the following 12-month period. Therefore, leaving the illness untreated is not as natural or as healthy as it might sound.

A hands-off approach is more likely to bring about marked interference with normal functioning than intervention with antidepressants. Again the ulcer model may help. Leaving an ulcer untreated for too long can lead to extensive scarring in the area around the ulcer. Even if the ulcer then heals, this scar tissue, by distorting the natural shape of the stomach and duodenum, can make future ulcers more likely and show their recovery.

Do antidepressants block important messages?

Another reason given for not taking antidepressants is based loosely on the biochemical theories of how they work? The argument goes that they block impulses flowing from one brain cell to another. This never sounds like a good idea to anyone. Other drugs which act on the brain, such as the major and minor tranquillisers do exactly this but antidepressants do not. They don’t block any messages any sort.

It should also be pointed out that chemical messages and psychological messages are not the same thing. As we age there are fewer neurotransmitters whizzing around our brains, but psychologically we remain the same.

Antidepressants and coping

A third argument goes, if antidepressants suppress or otherwise bring a halt to a depressive episode, surely the individual will not learn the coping skills that are necessary to handle depression and will therefore remain vulnerable to yet further depressive episodes. These latter depressive episodes will then increasingly have to be chemically controlled.

Regarding the question of whether antidepressants interfere with the development of natural coping mechanisms, the following points can be made. It would seem that depression is a demoralising disorder. It tends to be particularly demoralising the longer and more severe it is. Demoralisation is not something that antidepressants clear up. It typically resolves when the underlying depression evolves. At least, it does so when the underlying depression has not been so particularly severe and not so long lasting.

We spring back naturally. Springing back doesn’t came about because we have developed new coping skills. We simply don’t need to be anxious and demoralised once normality has returned. We are less likely to spring back in this way if the underlying depression has lasted a long time or been severe. In this case, antidepressants may clear up the sleep and appetite disturbances, and improve energy levels, but leave the person miserable, unhappy and with an impairment of self-esteem that may be more or less permanent. This impaired self-esteem will also make further serious and lengthy depressions more likely, as should the person ever become mildly clinically depressed again, the impaired self-esteem will summate rapidly with the depression, leading to a very rapid evolution of severe depression.

Therefore, everything possible should be done to avoid demoralisation. The best method of doing this is to insure that the depression as a person has is as brief and as mild as possible and in particular that they are not exposed to a severe or long-lasting disorder. The best advice therefore is that at the first hint that the disorder is not going to be brief  and self-resolving, some intervention is called for in order to preserve current coping skills and to prevent them being lost in the face of increasing demoralisation. This may be either a cognitive or interpersonal therapy or antidepressants, but it should be something rather than nothing.

Having made this point, however, the point also needs to be made that people who take antidepressants, and whose depressions resolve, should not conclude that the restoration of the self confidence they have had is all down to their antidepressant alone. Thinking this could lead on to a belief that one had to keep on taking the antidepressants in order to remain stable, or to a belief that one is more vulnerable than the average to further depression. Halting antidepressants if this were the case could be seen as the potential removal of a crutch, and it could become quite threatening. Such an idea of what antidepressants do would rob a person of confidence in their own resources to handle further episodes of depression, and even to handle episodes of interpersonal difficulties in general.

All too often, prescribers of antidepressants assume that because antidepressants do not cause a physical dependence or withdrawal symptoms, that there is no problem with prescribing them for lengthy spells. What we have all too often failed to realise is that depression causes a loss of self-esteem and that antidepressants do not necessarily put this right. If it comes right, it comes right in the way that anxiety clears up after an ulcer resolves. If it doesn’t come right, some consideration should be given to a psychological intervention rather than simply to more or longer courses of an antidepressant.

Return to normality

One of the hardest things for people to do after they have been depressed, whether or not they have been treated with antidepressants, but particularly if they have been, is to let themselves get normally depressed after they halt the drugs. We assume that we have been cured and should not get depressed again. The first hint of a poor day after stopping antidepressants often causes a serious panic and leads to a restarting of the pills. But returning to normal means returning to the normal ups and downs. What has to be relearned is an ability to live with these ups and downs, as they cannot be stopped. Even on antidepressants, the normal ups and downs should continue. The greatest block to recovery may be the idea of what it means to be well: ‘treatment should make me into someone who never has any ups or downs again’.

What if there is no response?

Before concluding that there is no response to an antidepressant, a subject should have been taking at least 150 mg of a tricyclic antidepressant for up to 6 weeks (see doses). If there is then definitely no response, the options are;

• To change to another type of antidepressant – an MAOI for example.
• To have a combination of antidepressants, for example a tricyclic along with an MAOI, or with mianserin, or with lithium.
• To go to a higher dose, as some people do not absorb the drugs as well or have other biological reasons why a higher dose is necessary (see doses).
• To add in a psychological therapy – paradoxically, many resistant ‘biological’ depressions seem to need the addition of psychological interventions.
• To discontinue antidepressants completely because although the person is very miserable and demoralised they do not have the kind of problem that responds to antidepressants. In this case, psychotherapy will be necessary.
• To have ECT. This remains the most effective treatment for depression. Today it is usually used as a treatment of last resort. But in fact, it has fewer side effects than any other physical treatment. It is used for example in the frail elderly or after heart attacks, where antidepressants may be contraindicated. As a treatment of last resort, however, it is sometimes given inappropriately to individuals who have failed to respond to medication but who should never have been given antidepressants in the first instance.

Doses

Tricyclic Antidepressants

The usual dose of a tricyclic antidepressant is 150 mg/day. In some cases, it is possible to start at 75 mg and increase to 150 mg within a few days. In others it is necessary to start at 25 mg and work up slowly. Everything depends on how sensitive the taker is to the side effects.

There is a trend toward giving the entire 150 mg in one dose, usually last thing at night. In the past it was more common to prescribe something like 50 mg t.d.s. or 25 mg t.d.s. and 75 mg at night. The rationale usually given for prescribing one dose at night is that the person will sleep through the side effects, but this doesn’t seem to be the case. If there are side effects, such as faintness or a dry mouth, these tend to be almost as severe the day after the night before as immediately after taking a daily dose. A better reason for giving antidepressants in one night-time dose is that they are somewhat sedative and may therefore assist sleep (see side effects). Another is that they work as well that the way as in divided doses, if not better. A third reason is that they are more convenient in a single dose.

If there is no response to 150 mg/day, in some cases the dose may be put up higher – anything up to 300 mg/day, depending on side effects. For most non-responders such an increase will make no difference. But for some, there is a failure to absorb the drug and larger doses are needed to produce normal blood levels. There are other factors that hinder recovery that may be overcome by a higher dose. These include high levels of the hormone cortisol, concurrent infections, concurrent treatment with contraceptives, and obesity.

Evidence suggest that there is little point being on less than 75 mg/day of a tricyclic. A little bit of an antidepressant just isn’t a little bit antidepressing.

On halting antidepressant, there are two options. One is to just stop in one go, even from a dose of 150 mg. This is possible because antidepressants are not addictive and there is essentially no withdrawal reaction, although there may be rebound effects. Because of these, it is more common to reduce the dose over a few days. Withdrawal from tricyclics may lead to cholinergic rebound, which may produce increased dreaming at night for 1-2 nights but little more. Occasionally, however, the reaction may be more pronounced, and stopping from a high dose may lead to sleeplessness and possible nausea.

MAOIs and RIMA

In the case of the MAOI, phenelzine, the effective dose is between 60 and 120 mg/day. For tranylcypromine it is 20-40 mg/day. For moclobemide the dose is 600 to 900 mg day in divided doses; it comes in 150 mg tablets. These are usually prescribed first thing in the morning, rather than last thing at night, as they may be mildly stimulant and interfere with sleep (see side effects).

Withdrawaş from an MAOI should pose no more problem than withdrawal from tricyclic, although phenelzine has something of a reputation of being more difficult, for reasons that have never been clearly pinpointed.

SSRIs: 5-HT Reuptake Inhibitors

The usual daily doses for selective serotonin reuptake inhibitors are:

• citalopram (20 mg)
• fluvoxamine (150-300 mg)
• fluoxetine (20 mg)
• sertraline (50-100 mg)
• paroxetine (20-30 mg)
• venlafaxine (37.5 mg, increasing to 75 mg twice a day if needed)

Withdrawal from an SSRI may lead to 5-HT rebound, the commonest symptoms of which are dizziness, headache, sweating and nausea. In the main these should be transient but there are some suggestions that a few individuals may have greater difficulties stopping an SSRI than other antidepressants – they may feel markedly more anxious and dysphoric.

Others

The usual daily doses for other antidepressants are:

• mianserin (60-90 mg o.d.)
• trazodone (150-300 mg o.d.)
• maprotiline (75-150 mg o.d.)
• nefazodone (100-300 mg b.d.)

The doses of lithium and other mood stabilisers are considered at a later stage.

Historical Note

The tricyclic antidepressant, imipramine, and the MAOI, iproniazid, were discovered in 1957 by Roland Kuhn and Nathan Kline respectively. What was discovered, however, was not just about a drug but a disorder that the drug treated. The reason for saying this is that neither the MAOIs or the tricyclics do anything much in the short term – therefore it was not obvious that they should be useful. There was no preconceived idea that these drugs should be antidepressant. Indeed Kuhn thought he was testing out a new neuroleptic when he first gave imipramine to patients. Furthermore, there were a great number of euphoriants available at the time, such as amphetamines, but these did not appear particularly helpful for depression. What Kuhn and Kline did then, as much as find the compounds themselves, was to make visible a condition that responded to these compounds. It is this condition, variously called biological or major depression, which is in many respects the source of difficulties in specifying what the antidepressants do. We still do not know the nature of depression or its boundaries.

In 1965, the Medical Research Council (MRC) reported the outcome of a large multicentred study to compare the MAOI, phenelzine, with imipramine, ECT and placebo. Imipramine and ECT came out as superior to placebo and phenelzine, with phenelzine being no netter than placebo. This along with the recognition of the cheese effect of MAOIs (see side effects), which was emerging at the same time, more or less put paid to the MAOIs, leaving the tricyclics as the dominant antidepressants for over two decades.

Many clinicians, however, having seen a great number of patients respond to MAOIs found it hard to believe that these drugs were ineffective. The view developed that the MAOIs might be specifically beneficial for anxious depressions or atypical depressions – a view encouraged by the drug companies producing MAOIs.

However, there was a flaw to the MRC study in that too low a dose of phenelzine was used – 45 mg in contrast to the 90 or 120 that is more customary now. Studies that used a more adequate dose have subsequently found the MAOIs to be as effective for major depressive disorder as the tricyclics, with little indication that they treat a different form of depression to the tricyclics. The distinctions have also been blurred by an increasing recognition that the tricyclics may be of significant benefit in anxious depressions also.

It remains the case, however, that there are some people who respond to MAOIs who do not respond to tricyclic antidepressants. Clear-cut cases of major depressive disorder that might be expected to respond to a tricyclic sometimes do not, despite changing the drug several times and lengthy trials at adequate doses. When given an MAOI, however, there may be a prompt response. The reverse also appears to hold true.

The 5-HT Reuptake Inhibitors (SSRIs)

In the early 1960s, it was discovered that tricyclic antidepressants blocked the reuptake of the neurotransmitters noradrenaline and 5-HT. Subsequently, it was shown that the first two tricyclics, amitriptyline and imipramine, broke down in the body to nortriptyline and desipramine. Nortriptyline and desipramine both turned out to be antidepressants. This suggested that these were in fact the real antidepressants rather than imipramine and amitriptyline.

Both nortriptyline and desipramine also turned out to block the uptake of noradrenaline, but not 5-HT. The logical conclusion was that depression involved a disturbance of noradrenaline rather than 5-HT function. This observation led to the cateholamine hypothesis of depression, and to a belief that the production of further antidepressants should focus on producing compounds that manipulate the noradrenergic system. But in a marvellous example of ignoring the theories of how things work and focusing instead on whether they work, Arvid Carlsson from the Karolinska Institute in Sweden, noted that while it appeared that nortriptyline and desipramine must be the core antidepressants, clinicians appeared to prefer amitriptyline and imipramine. Why?

Looking at these compounds, he pinpointed the inhibition of 5-HT reuptake as the one thing amitriptyline and imipramine did which nortriptyline and desipramine did not. He proposed that drugs selectively blocked 5-HT reuptake should be produced. This led to the production of zimelidine in the early 1980s which was marketed as an antidepressant and appeared to work but had to be withdrawn because of side effects. It has since been succeeded by fluvoxamine, fluoxetine, sertraline, citalopram and paroxetine.

There is, however, no good indication that blocking 5-HT reuptake is necessary for an antidepressant action. There is, for example, no correlation between how effective these drugs are at blocking 5-HT reuptake and how quickly or how effectively they cure depression. The reason why so many of these compounds are being produced has probably more to do with marketing and legal issues than with ’science’. This point is developed further in section 9. The term SSRI was coined by investigators working with paroxetine. This seemed like a good marketing angle and was exploited first by SmithKline Beecham, but the use of the term spread thereafter to cover all the drugs in the group, even though strictly speaking none of them are absolutely selective to the 5-HT system.

It is worth briefly considering the SSRI story a bit more in order to bring out the difficulties in specifying what antidepressants do. Before zimelidine, clomipramine was the tricyclic antidepressant that most effectively inhibited 5-HT reuptake. This had been produced by Geigy in the 1960s, but it seemed no more effective than other antidepressants and it appeared if anything to have more side effects. So much so that it was not licensed for release in the USA until 1990. This left the company with a marketing problem. Their answer was to produce an intravenous preparation of clomipramine and to encourage prescribers to give it in large doses intravenously. The outcome of this was a discovery that it seemed to be in some way anxiolytic – it was found to be useful in phobic and obsessional states.

Are 5-HT reuptake inhibitors, then, in some way anxiolytic rather than, or in addition to, being antidepressant? There is a good deal of evidence that manipulations of the 5-HT system either cause anxiety or alleviate it. If blocking 5-HT reuptake is anxiolytic, this might explain why clinicians prefer tricyclic antidepressants that also block 5-HT uptake to those that do not, as most depressed patients are anxious as well as depressed.

There is further possibility. Given that we now know that most depressions resolve with time anyway, perhaps treatment with an anxiolytic might promote recovery in most cases. That anxiolytics might in other words be antidepressants! There is a considerable amount of evidence that treatment with agents that reduce anxiety or agitation may be all it takes to get many depressions better. It is on this basis that benzodiazepines and neuroleptics may be of benefit in depression. Many, although not all clinicians, would think that there is something more to antidepressions, such as imipramine or phenelzine, than just anxiolysis, but exactly what antidepressants do over and above alleviating anxiety has been very difficult to specify.