The most common treatments for depression are drugs. We will look at the three types of drugs used:
- tranquillisers; and
- antimanic drugs or ‘mood stabilisers’.
There are several separate families of antidepressants and various antidepressant drug classes whose effectiveness ranges across the depressive sub-types. For this reason, antidepressants should not be discounted if one particular type does not work. Even if two antidepressants fail, a careful review should be undertaken. This could show that the patient would benefit from another antidepressant drug, or a combination of drugs.
Although there is no universal method of labelling drugs, antidepressants can be broken down by generation, chemical characteristics and the function of the drug. Drug ‘generation’ refers to the period of the discovery of the drug and its formal release. Thus, the ‘first generation’ antidepressants emerged in the late 1950s and were extensively trialled in the 1960s. The second generation antidepressants emerged in the late 1970s and early 1980s, while the third generation drugs have generally been available only during the last decade.
The defining chemical characteristics of the drug classes are determined by their nuclear structure. ‘Tricyclic’ drugs have a three-ring structure, ‘tetracyclic’ four, and recently developed ‘bicyclic’ drugs have a two-ring structure.
The third element underpinning an antidepressant’s label refers to the function of the particular drug. For example, drugs that block the enzyme monoamine oxidase (MAO) are subdivided into those that block the enzyme irreversibly (the MAOIs) and those that do so reversibly (the RIMAs). While most antidepressants have multiple actions, many work by inhibiting the reuptake or reabsorption of different neurotransmitters (including serotonin, noradrenaline and dopamine) at the nerve synapses, thus increasing the concentration of that particular neurotransmitter. The first generation antidepressants (the tricyclics and MAOs) act on multiple neurotransmitters. The newer drugs, on the other hand, are more selective in the neurotransmitters they target. This selectivity is captured in the drug class name, such as Selective Serotonin Reuptake Inhibitors (SSRIs).
Are all antidepressants of equal benefit?
Formal trials comparing one drug class against another have allowed many scientific reviewers to conclude that all antidepressants are of equal benefit, and that their differences are due to varying side-effects. The Mood Disorders Unit would argue, however, that the different antidepressants are not of equal benefit. The ‘equal benefit’ view is largely built on data from drug trials, where relatively ‘pure’ cases of depression are examined, which are often less severe than those seen in clinical practice. Also, patients with melancholic and psychotic depression are rarely included in clinical trials. When data are collected from ‘real world’ clinical practice studies, a different picture emerges—one that shows the different classes of antidepressants varying considerably in their effects on the different types of depression.
Currently available antidepressant drugs
First generation antidepressants
Irreversible Monoamine Oxidaze Inhibitors (MAOIs)
Second generation antidepressants
Third generation antidepressants
Selective Serotonin Reuptake Inhibitors (SSRIs)
Serotonin and Noradrenaline Reuptake Inhibitors
Reversible Inhibitors of Monoamine Oxidase-A
Other drug types
Noradrenaline Reuptake Inhibitor (NARI)
Dopamine-Noradrenaline Reuptake Inhibitors (DNRIs)
Noradrenergic and Specific Serotonergic
Antidepressants and non-melancholic depression
Some of the newer antidepressants (especially the Selective Serotonin Reuptake Inhibitors, or SSRIs) seem to be equally as effective as the older first-generation antidepressants, may be more readily tolerated in terms of side-effects than the first generation antidepressants and may have beneficial effects beyond treating the depression, for example by decreasing worrying, brooding and irritability.
People with an ‘anxious worrier’ personality style commonly state that the SSRIs induce a sense of detachment from their problems. The problems are still there, but instead are viewed as if by a non-worrier, so that the individual feels that they are swimming rather than sinking. This means that patients worry less, or for briefer periods, so decreasing the chance of worry developing into a depression. If the patient is already depressed, SSRIs may make the depressive episodes briefer and more manageable. The SSRIs also seem to help a significant percentage of those who externalise their anxiety with bursts of irritability.
Antidepressants and melancholic depression
The older Tricyclics (TCAs) and Irreversible Monoamine Oxidase Inhibitors (MAOIs) appear to be more effective than the SSRIs for melancholic and psychotic depression, but tend to have more side-effects. The effectiveness of a number of the other, newer antidepressants for these depressive sub-types is less clear. Some may be too refined in their action, unlike the first-generation antidepressants, which impact on multiple neurotransmitters. Unfortunately, their impact on multiple neurotransmitters also increases the range of possible side-effects.
The first generation antidepressants have also been shown to be more effective in older patients, those who have had multiple episodes, and when PMD is severe.
It would be reasonable for an individual with a first episode of melancholic depression to be commenced on an SSRI or a Serotonin and Noradrenaline Reuptake Inhibitor (SNRI). If treatment is successful, it can be recommenced for any subsequent episodes. If this first-line treatment fails, then TCAs and MAOIs should be considered.
Antidepressants and psychotic depression
It is generally not enough to treat psychotic depression with antidepressants alone. Most cases of psychotic depression will require a combination of drug therapies, for example, an antidepressant and a tranquilliser. In some cases, electroconvulsive therapy (ECT) may be needed.
Augmentation of antidepressant drugs
The effectiveness of some antidepressants can be increased by the use of adjunctive or augmentation drugs, for example, thyroid hormones or lithium. There is increasing evidence to suggest that the new ‘atypical’ antipsychotic drugs may also have augmenting effects on antidepressants, often working rapidly and also being able to be ceased rapidly in many instances. While not investigated formally, the benefits of such augmenting drugs may only be relevant to melancholic and psychotic depression.
How useful is St John’s Wort (hypericum) as an antidepressant?
In May 2000, the popular herbal remedy St John’s Wort was evaluated as an antidepressant.1 The evaluation was based on fourteen trials involving over 1400 adults. In eight trials subjects were given St John’s Wort or a placebo, while in the other trials St John’s Wort and a tricyclic antidepressant. The doses of St John’s Wort ranged from 300–1800 mg/day.
‘Responders’ were defined as those whose condition had improved by 50 per cent or more. The aggregated studies indicated that 38 per cent of those receiving a placebo were responders, compared to 62 per cent of those receiving St John’s Wort and 61 percent receiving the tricyclic antidepressant. Such data would seem to indicate that St John’s Wort is an effective antidepressant (being significantly superior to the placebo) and of comparable effectiveness to the tricyclic antidepressants. However, as trials were generally undertaken on those with mild depression, St John’s Wort is likely to be of possible assistance only to a percentage of people experiencing non-melancholic depression.
As yet, no formal trial has compared St John’s Wort to an SSRI, but such data are expected to emerge in the next year. While the status of St John’s Wort as an antidepressant remains to be clarified, its effectiveness is likely to be limited to non-melancholic depressive disorders.
St John’s Wort can have side-effects, however, and there are now several reports suggesting that it may have some toxic effects on reproductive functioning. As with any drug, care should be taken to consider its side-effect profile.
How quickly do antidepressants work?
Most treatment guidelines suggest that antidepressants may take many weeks to work. It is argued that even if the current treatment seems ineffective, it should be persisted with for several weeks or even months. The Mood Disorders Unit interprets the evidence differently.
If medication is likely to be effective, evidence of at least some improvement should appear in the first ten days or so, whether it be an improvement in mood, sleep or other features.
For melancholic and psychotic depression, the rate of improvement is generally slower (but relatively constant). It may, in fact, appear painfully slow.
If no improvement is noted in the first two weeks after commencing an antidepressant, the dose of that drug may need to be increased, a change to another class of antidepressant may be required, or ‘augmenting’ strategies (the addition of quite differing drugs) may need to be introduced. Unfortunately, when changing from one drug to another, days to weeks may pass before success can be established. It might also be the case that non-drug strategies will be more effective in bringing the depression to an end.
Antidepressant drugs are significantly different from the class of drugs known as tranquillisers. This class can be divided into minor and major types.
Most of the minor tranquillisers belong to a family of drugs called benzodiazepines, examples of which include Ativan, Ducene, Mogadon, Murelax, Normison, Rivotril, Rohypnol, Serepax, Temazepan, Valium and Xanax.
Benzodiazepines are addictive, and may exacerbate depression, or interfere with the normal grief process. In recent years, they have been greatly overused, leading to an understandable suspicion of psychiatric medication. An unfortunate effect of this over-prescription has been a misplaced fear of antidepressants, as people don’t understand that, unlike tranquillisers, they are not addictive.
The major tranquillisers (also known as neuroleptic or antipsychotic drugs) are of particular benefit in treating psychotic depression when administered together with an antidepressant.
The newer ‘atypical’ antipsychotic drugs have a different side-effect profile, generally making them more tolerable to patients. As well as being effective in treating psychotic depression, they may also be of some assistance in instances of treatment-resistant melancholia. If they are effective, results are often rapid.
Antipsychotics are thought to work by blocking the action of a neurotransmitter dopamine. There are two main groups of antipsychotics—typical and atypical.
The term ‘atypical’ has many meanings. As a class, these drugs are serotonin–dopamine antagonists (SDAs), interacting with key brain dopamine pathways. They have different side-effects to older ‘typical’ antipsychotics; in particular, they are less likely to cause muscle stiffness, and appear safe and more able to be tolerated.
✰ Antimanic drugs or mood stabilisers
Bipolar disorder affects about 1–2 per cent of adults in the community, with more than 50 per cent of these people likely to experience the condition before the age of 30.
By decreasing both the frequency and amplitude of the mood swings, the antimanic medications lithium, valproate and carbamazepine (usually called mood stabilisers) are generally viewed as equally effective in the treatment of bipolar disorder.
(Lithium is also used to strengthen [or augment] antidepressants when they are ineffective in dealing with unipolar depression. Such a role appears to be of likely benefit only to those with melancholic depression.) It has been suggested that each treatment may have specific advantages, depending on their different side-effects and the profile of the disorder.
Many patients who do not respond to or tolerate a particular antimanic medication will usually do well with one of the others, while patients with severe cases of bipolar disorder may require combination therapies. Particularly severe cases may require the additional use of one of the major tranquillisers.
Antimanic medications are effective in both treating episodes of mania and preventing relapses into mania and depression. When unsuccessful, combinations of mood stabilisers, or the introduction of more experimental mood stabilisers (for example, lamotrigine and topiramate) may be trialled. (These drugs are experimental in the sense that their clinical effectiveness and utility are still being clarified.) When someone is experiencing a manic episode, all mood stabilisers generally take several weeks or more to work. For this reason, it is usually necessary to also prescribe a calming medication, such as a tranquilliser, which is then withdrawn once the mania settles. Someone experiencing mania often has no awareness or insight into the changes of behaviour that are occurring. The patient cannot understand the need for treatment—a need that is obvious to friends and family. Recovery takes at least several weeks, sometimes months. For someone with a first-onset episode, six months of ongoing treatment may be sufficient to prevent a relapse. The more severe or frequent the episodes, the more compelling the argument for long-term treatment.
Some people with bipolar disorder find it difficult to take the mood stabiliser regularly. This may be due to a reluctance to accept the diagnosis or the need to take medication regularly, or to see whether they can manage without tablets.
Called ‘poor compliance’, it is a common reason for relapsing into a new episode. (In such cases, it is important to understand why the medication was stopped.) Others, however, experience further episodes despite excellent compliance.
Patients and families need to understand that most people who experience a manic episode will have further episodes of mania and/or depression.
✰ Commonly asked questions about drug treatments
Three of the most common questions asked by patients when discussing their drug treatments are:
- Must I take medication?
- How long will I need to stay on medication?
- Which drugs should I consider and what are their side-effects?
✰ Must I take medication?
There is no general rule about the need to take medication.
Someone who presents with a recent non-melancholic depression that came on after a major stressor, and who has few clinical symptoms, will often do well without the need for antidepressants.
If, however, depression came on for no good reason, sleep patterns are affected, lack of emotional control is making the condition worse, or the doctor thinks the patient might have a melancholic depression, then it would be best to trial an antidepressant.
With non-melancholic depression, there is no one treatment. It’s a bit like deciding what to do when a car runs off the road into a ditch. If advice to rev the engine (counselling, psychotherapy) is moving the car back towards firm ground, fine. But if all that is happening is that the wheels are spinning, it’s better to put a sack under the tyres to aid grip or call a tow-truck (medication) as well. Many antidepressants, particularly the SSRIs, act on a patient’s predisposing and perpetuating personality traits (such as ‘worrying’). They may therefore indirectly prevent the onset—as well as shorten the duration—of depressive episodes.
When deciding to stop taking an antidepressant, the patient must check how to taper the dose. Suddenly ceasing all medication without slowly decreasing the dose can lead to severe emotional and physical reactions including anxiety, agitation, insomnia, severe sweats and racing heart. For some medications, even missing one dose can initiate a ‘withdrawal reaction’.
For melancholic or psychotic depression, the advantages and need for physical treatments are distinct, with recovery quite unlikely to occur otherwise.
✰ How long will I need to stay on the medication?
There are many treatment guidelines that pronounce strict rules, including views that individuals should remain on medication for life if they have experienced either one severe depressive episode or a number of episodes. Such rules are too prescriptive and restrictive for many of those affected. However, there is an argument for extended medication treatment if a single episode of depression
- was extremely severe;
- put the patient at considerable risk and compromised their functioning for an extended period; or
- was extremely difficult to treat.
In contrast, however, a patient may have had numerous depressive episodes precipitated by social factors. At some stage in the recovery process, these social factors become irrelevant. In such cases, it is difficult to argue that antidepressant medication should be taken for an extended period.
Decisions on how long a patient should receive medication should therefore be made on a case-by-case basis. The prescribing clinician will need to decide what medication will be needed to ensure ‘recovery’ from a particular episode, as well as whether there is a need for ‘continuation’ and ‘maintenance’ medication to prevent subsequent episodes. Large samples of data are available to help the clinician on such issues, but the very fact that the samples are based on grouped data means that they should be used just as a guide. Once a patient has recovered, the decision whether or not to alter the dose or stop the drug will depend on the individual case.
✰ Which drugs should I consider and what are their side-effects?
The decision on which drugs to take is best decided between the individual and their treating doctor. Most drugs generate lengthy lists of possible adverse effects, even though the probability of a patient developing most of them is, at worst, slight and in most cases negligible.
However, some antidepressant drugs have potentially very severe side-effects, particularly if taken in conjunction with other drugs. It is the responsibility of the treating clinician to address these issues at the individual level.
For those seeking reference material on the side-effects of drugs, drug interactions and drug safety during pregnancy and breastfeeding, two publications are recommended: Psychotropic
Drug Guidelines and The Maudsley Prescribing Guidelines
Most pharmaceutical companies provide quite detailed product information leaflets addressing side-effects and commonly raised questions about individual drugs. Bimonthly and yearly MIMS Manuals (Monthly Index Medical Specialty) give detailed and abbreviated information on drug side-effects and related issues.
(extracted from) Dealing with Depression: A Commonsense Approach to Mood Disorders by Gordon Parker, published by Allen & Unwin