Depression is a common (Singleton 2001), disabling (Spitzer 1995; Cassano 2002), costly (Murray 1997; Thomas 2003) and under-treated condition (Singleton 2001; Bebbington 2000; Demyttenaere 2004; Wang 2005). The health burden of depression is recognised by the World Health Organisation (WHO) and several national programme objectives in individual European states as a priority for health in the 21st century. Depression is characterised by depressed mood or loss of interest or pleasure in nearly all activities in the presence of other symptoms such as loss of appetite, fatigue and lack of energy, sleep disturbance, restlessness or irritability, feelings of worthlessness or inappropriate guilt, difficulty thinking, concentrating or making decisions and thoughts of death or suicide or attempts at suicide (APA 2005).
Only about 30% to 40% of people in the community who meet diagnostic criteria for depression receive any form of medical or psychological treatment (Singleton 2001; Lin 1999) and this falls to 25% or less when only treatments judged to be of minimal adequacy or better are included (Young 2001). Talking therapies are popular and effective but are still in short supply in community settings in the UK.
Depression is considered to be the result of depletion in the levels of serotonin, noradrenaline and/or dopamine in the central nervous system. Antidepressant drugs elevate the levels of these neurotransmitters in the brain by blocking their re-uptake in the synaptic cleft; all have all been shown to be effective in the alleviation of depressive symptoms. However, there is still considerable doubt about the precise role of the monoamine neurotransmitters in depression (Delgado 2000). There has also been a reluctance to use other chemicals, such as psychostimulants, to increase monoamines concentrations and function, usually because of fears of misuse or dependence.
The current first line of drug treatment for moderate or severe depression is antidepressants such as selective serotonin reuptake inhibitors (e.g. fluvoxamine, sertraline, citalopram) or tricyclic and related antidepressants (e.g. amitriptyline, imipramine, lofepramil) (NICE 2004). Monoamine oxidase inhibitors (e.g. phenelzine, moclobemide) may also be useful. However, there are a number of problems with their use:
• There is evidence for the efficacy of antidepressant drugs but their clinical effect may be weak (Moncrieff 2005), adherence to treatment is poor (Maddox 1994) and approximately one third of patients who adhere to treatment do not recover.
• Antidepressants take between one and three weeks to have full effect.
• Reduced energy is a core feature of depression but many antidepressants do not alleviate this symptom. Fatigue may also be a complication of therapy with antidepressants. This disadvantage is particularly important in people with co-morbid physical illness.
Psychostimulant drugs are a possible alternative to antidepressants. However psychostimulants are often limited in the conditions they can be used for. Currently in the UK they are only licensed for use in the treatment of attention-deficit hyperactive disorder (BNF 2007). Psychostimulants (PS) increase synaptic activity of the monoamine neurotransmitters, dopamine, noradrenaline and serotonin. They have an indirect agonist effect by increasing neurotransmitter function rather than a direct effect on postsynaptic receptors. All produce a similar increase in monoamine activity. The main advantage of psychostimulants over selective serotonin reuptake inhibitors and tricyclic antidepressants may be their time course of action. Psychostimulants appear to act quickly; some patients report an improved sense of well being within 24 hours. They may also promptly reduce fatigue and increase energy, benefits that may be crucial in those with severe physical illness or in older people (Nguyen 2005).
Why psychostimulants are not considered a treatment option in depression (NICE 2004) may relate in part to uncertainty about their effectiveness and safety:
• Earlier reviews of the evidence on effectiveness of psychostimulants for depression have reported inconsistent results across studies (Chiarello 1987; Linet 1989; Masand 1998; Postolache 1999; Satel 1989)
• There is potential for misuse, dependence and associated withdrawal reactions
• Current legislation in the United Kingdom means that most psychostimulants are controlled substances.
We believe it is time to review the place of psychostimulants in the treatment of depression and to decide whether further research to evaluate their efficacy in particular settings, such as palliative care, may be indicated.
B Candy, L Jones, R William, A Tookman, M King
Cochrane Database of Systematic Reviews 2007 Issue 4
DOI: 10.1002/14651858.CD006722 This version first published online: 18 July 2007 in Issue 3, 2007
Date of Most Recent Substantive Amendment: 25 April 2007
This record should be cited as: Candy B, Jones L, William R, Tookman A, King M. Psychostimulants for depression. (Protocol) Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006722. DOI: 10.1002/14651858.CD006722.
