Depression

Treatment

 Pharmocotherapy
 Psychotherapy

Pharmacotherapy

Effective treatment of depression usually requires a combination of pharmacotherapy and counselling or psychotherapy.

A large number of effective drugs are available for the treatment of depression, and these can be subdivided into several main categories:

It is important to realise that antidepressant drugs do not act immediately, in the way that, for example, analgesics do. It may take about 4-6 weeks of treatment before significant improvement in symptoms is noted. In addition, treatment should be continued for 6-9 months or possibly longer, to ensure complete recovery and to prevent recurrence of depression.

Select the drug type you are interested in from the table above for more information.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are believed, by some clinicians, to be the most potent agents in the treatment of depression and anxiety, with phenelzine as the drug most frequently prescribed for many of these disorders (Bakish et al., 1998). These agents are effective in the treatment of these disorders, although their use may be limited due to their considerable side effects and the rigid dietary restrictions required when taking them (Jefferson, 1997). The classical MAOIs are not considered first-line treatments for depression or anxiety.

Moclobemide, a reversible selective inhibitor of monoamine oxidase A (RIMA), which binds with MAO _A, thereby leaving MAO _B free to metabolise tyramine (thus eliminating the need for dietary restrictions) has been proven to be effective in a wide range of depressive and anxiety disorders such as panic disorder and post-traumatic stress disorder (Tiller et al., 1997; Priest et al., 1995). However, in recent studies, the efficacy of this agent has been disputed (Schneier et al., 1996; Noyes et al., 1997).

In general, physicians avoid initiating therapy with MAOIs. MAOIs are seen as second-line therapies and many physicians are alarmed by the potential risks associated with the interaction with the amino acid tyramine and feel that the dietary restrictions this imposes are impractical. Some psychiatrists, however, are more willing to use these agents, especially in patients whose depression is resistant to other therapies.

The RIMA, moclobemide (Manerix, Aurorix), in contrast to the older MAOIs (eg phenelzine (Nardil), isocarboxazid (Marplan) and tranylcypromine (Parnate)), binds reversibly to the MAOA enzyme and therefore has a shorter duration of action which improves safety and reduces the washout time required before the initiation of a different antidepressant. This becomes relevant when it is necessary to switch non-responders to a new antidepressant.

Older MAOIs

The older MAOIs are associated with a potentially fatal side effect known as the 'tyramine effect' (from the Greek word tyros, meaning cheese). The most important characteristic reaction associated with the tyramine effect is the hypertensive crisis. These crises are characterised by some or all of the following symptoms:

• headache
• palpitations
• neck stiffness or soreness
• nausea, vomiting
• sweating (sometimes with fever and sometimes with cold, clammy skin)
• dilated pupils and photophobia (sensitivity to bright light).

Tricyclic Antidepressants (TCAs)

The TCAs (imipramine, amitriptyline, doxepin, desipramine and clomipramine) are well-established in the treatment of depression but also in treating panic disorder and other anxiety disorders. TCAs act by inhibiting the uptake of both noradrenaline  and serotonin in the synaptic cleft. TCAs with strong antihistaminergic properties, such as doxepin and amitriptyline, have sedative properties that are useful when treating patients with insomnia.

Disadvantages of the TCAs may include daytime sedation, anticholinergic side effects, orthostatic hypotension, cardiotoxicity, toxic psychosis and initial worsening of the condition. All these factors have been found to lead to relatively poor compliance. Other side effects such as impairment of cognitive skills and psychomotor abilities may have profound implications on the patient's day-to-day activities such as driving and operating machinery and TCAs should be used with care in the elderly. The TCAs may interact with several other agents including MAOIs, alcohol, oral contraceptives and anticholinergic drugs, which further limit their use (Bakish et al., 1998). The risk of lethal overdose with these drugs is more troublesome than with most of the newer drugs.

For the reasons listed above TCAs are not generally considered as a first-line treatment option in depression (Bakish et al., 1998).

However, the antidepressant market, in terms of number of prescriptions written, is dominated by TCAs. One will therefore encounter many physicians who are already apparently satisfied with these antidepressants, mainly due to economic considerations.

TCAs are widely seen as the 'standard' against which the efficacy of other antidepressants is measured. However, their significant anticholinergic effects and the risk of fatality in overdose are widely acknowledged. Most physicians warn their patients about the likely side effects, especially the drowsiness and anticholinergic effects, in the hope that patients will be prepared for them and will continue with therapy despite them. Despite physicians' experience, data from the marketplace show the vast majority of scripts are written for subtherapeutic doses. First-generation TCAs, especially amitriptyline and dothiepin (Prothiaden) tend to be the most sedating and may cause severe daytime drowsiness. Some physicians see this as an advantage, however, because they think this is likely to improve sleep and alleviate symptoms of depression and anxiety. Second-generation agents such as lofepramine (Gamanil) are less sedating, and some physicians regard them as more suitable for elderly or lethargic patients.

Tetracyclic Agents

Trazodone is a modified tetracyclic in a class of its own. At subtherapeutic doses it is a serotonin antagonist but at therapeutic doses it inhibits serotonin reuptake.

Selective Serotonin Reuptake Inhibitors (SSRIs)

The SSRIs have been on the market for depression treatment for over two decades. The drugs in this class share the common mechanism of therapeutic action of inhibition of serotonin reuptake, as illustrated below (Stahl, 2000).

Although all the drugs in this class inhibit serotonin reuptake, their respective selectivity for this site varies markedly. The following descriptions of the compounds in this class includes an illustration of their respective spectrum of receptor activities; in many cases, the varied side effect profile observed for each compound can be explained by this 'additional' activity at sites other than the serotonin reuptake sites.

The following diagrams illustrate how the various SSRI compounds on the market exhibit distinct receptor activity at sites other than the serotonin sites.

Fluoxetine
Fluoxetine (Prozac) is not only a serotonin reuptake inhibitor but may have important secondary actions at 5-HT _2C receptors, perhaps by directly stimulating them. At very high doses, it may also inhibit noradrenaline reuptake. In the normal dose range, it is an inhibitor of both CYP450 2D6 and 3A4 (Stahl, 2000).

Fluvoxamine
Sigma receptors are thought to be active in modulating cholinergic, glutamatergic, as well as dopaminergic neurotransmission. In animal models, there are suggestions that sigma receptors are involved in learning and memory, psychosis, aggressive behaviours and anxiety. Agents for which sigma properties may be relevant include especially fluvoxamine but also perhaps, sertraline (Stahl, 2000).

Paroxetine
This compound may have mild degrees of muscarinic, cholinergic antagonist properties. It remains unclear whether this may also cause clinically relevant noradrenaline reuptake inhibition. Nitric oxide synthetase and CYP450 2D6 are also inhibited by paroxetine (Stahl, 2000).

Sertraline
This SSRI has dopamine reuptake inhibition effects, as well as some sigma receptor activation (Stahl, 2000).

Citalopram
Among the currently available SSRIs on the market, citalopram has the most selective profile for the serotonin receptor, which is in accordance with its benign side effect profile (Joubert et al., 2000).

The SSRI Class of Antidepressants

SSRIs are as effective as TCAs in the treatment of most depression and anxiety disorders, but have fewer side effects (Anderson and Tomenson, 1995; Montgomery and Kasper, 1995). The more attractive safety profile of the SSRIs enhances patient compliance, which in turn improves the treatment outcome with these agents. Due to the increased risk of side effects, non-compliance is high with the TCAs.

Although some physicians, patients and patient groups prefer the TCAs to SSRIs, due to their lower cost per dose, recent studies have shown that when all service costs for depressed patients are calculated, SSRIs are no more costly to the healthcare system than the TCAs (Jönson and Bebbington, 1993).

Find out more about the mechanism of action of SSRIs

Serotonin-noradrenaline Reuptake Inhibitors (SNRIs)

Serotonin and noradrenaline reuptake inhibitors act by blocking reuptake of both neurotransmitters (and also dopamine to some degree). In vitro they reduce receptor sensitivity after only one dose.

Noradrenaline Reuptake Inhibitors (NaRIs)

This new class of antidepressants, represented by reboxetine, selectively inhibits the uptake of noradrenaline, increasing the availability of noradrenaline in the synapse and so enhancing noradrenergic transmission.

Noradrenaline and Selective Serotonin Antidepressants (NaSSAs)

Noradrenaline and selective serotonin antidepressants (NaSSAs) enhance noradrenergic and serotonergic neurotransmission. Mirtazapine is currently the only agent available in this class.

Atypical Agents:

These include Monocyclic aminoketones and postsynaptic 5-HT2 receptor antagonist and presynaptic SSRIs.

Side Effects of Antidepressants

Antidepressant drugs produce a range of side effects, including dry mouth, blurred vision and altered bowel function (diarrhoea or constipation). Many of the side effects are transient (such as nausea caused by SSRIs), but some seem to be stable over time (sexual side effects) and may affect long-term compliance. If any of these occur, the physician has to decide upon the most appropriate action, e.g. reducing the dosage or switching to a different drug.

Discontinuation of SSRI Treatment

The effect of discontinuation of SSRIs and TCAs should be considered for each patient. Citalopram, like all SSRIs and TCAs (except perhaps fluoxetine), requires a controlled withdrawal period, and it is recommended that the dose of the drug is reduced gradually while monitoring discontinuation symptoms. The mnemonic 'FINISH' has been suggested (Berber, 1998) to increase awareness of this problem, focusing on symptoms such as Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances and Hyperarousal (agitation/anxiety) which may be associated with SSRI treatment discontinuation.

This should not be confused with withdrawal or addiction. These drugs do not cause tolerance, where the patients needs increasingly higher doses of a substance/drug to keep getting the same effect, as seen with alcohol and benzodiazepines.

Psychotherapy

Many people with depression find that a course of counselling can help them to identify why they have become depressed. Counselling, used in addition to antidepressant drugs, is an important part of the treatment of depression. It can assist recovery and reduce the chance of recurrence. Just as no two people have exactly the same symptoms of depression, their needs for counselling also differ. Counselling may take many different forms. For example, someone who has become depressed following the death of a loved one might need help to come to terms with their feelings of loss and grief, while someone with feelings of anxiety might be taught relaxation techniques.

Counselling should also include basic information about the course, risk of relapse and recurrence, importance of maintenance treatment and possible signs of recurrence. Genetic counselling is becoming increasingly important to address as awareness of depression increases within the medical field and in the general public.

Depression can be a difficult illness for family and friends to understand. It is confusing and distressing for them to see someone they love become withdrawn and irritable, and show no interest in activities that he or she previously enjoyed. Involving them in treatment or counselling is also important.

Psychotherapeutic Interventions

The psychotherapeutic interventions are an essential part of the treatment programme and should always be considered as a parallel to the pharmacological treatment. Psychoeducation aims to give the patient an understanding of the afflicting disorder and the role of all forms of therapy in the treatment, to full remission, of the disorder.

The recent development of cognitive behavioural therapy (CBT) has lent further support to the non-pharmacological management of patients. There have been studies reporting the comparisons of CBT with pharmacological treatments and although some of these indicate that in the short-term the pharmacological treatments have a superior effect, this effect may diminish in longer treatment programmes. Ideally a patient should receive both psychotherapeutic interventions, like CBT, and pharmacotherapy (Borkovec and Costello, 1993).

For the psychotherapeutic treatment of anxiety each case needs to be considered individually, according to the type, severity and chronicity of symptoms, triggers that elicit or aggravate the symptoms, life stressors, coping ability, learning potential, specific personality traits and motivation to change. Different approaches may be necessary for patients with predominantly psychic symptoms compared with those needed for patients who also exhibit strong somatic symptoms. In addition, different medications may be required for the individual somatic symptoms, e.g. cardiac, gastrointestinal or muscular symptoms.

Further studies are needed of SSRIs versus CBT and the combination of the two treatments. None exist thus far with citalopram and CBT.

Factsheet: Treating mental disorders

Last updated: 20.12.2011