The mechanisms of action of drugs used in the treatment of affective disorders
The noun affect refers to feelings or emotions (Carlson, 2001) thus affective disorders involve either flattening or excesses of emotions. They involve the extremes of elation (mania) and despair (depression); with unipolar disorders being single directional mood changes - mania or depression. Bipolar disorders, by contrast, involve mood swings in both directions (Rang et al., 1999), hence manic depression; and are life long illnesses that require long-term treatment (Vieta & Goikolea, 2005).
Bipolar disorder sufferers (manic depression) experience periods of mania lasting for days to months, followed by periods of depression lasting 3 times that long (Carlson, 2001). These major depressive episodes (MDE) are associated with high morbidity, mortality and increased suicide (20% of patients succeed- e.g. 30 times higher than general population) (Amsterdam & Shults, 2005).
The goal of drug treatment of affective disorders is to maintain an even mood so that extremes are not experienced. This is achieved principally by targeting the monoamine system, with 4 main types of drugs being used currently tricyclic antidepressants, 5-HT uptake inhibitors, monoamine oxidase inhibitors and atypical antidepressants.
Monoamine theory of depression
The monoamine theory of depression was proposed in 1965 and suggests that depression is caused by a functional deficit in monoamine transmitters in key areas of the brain, whilst mania is the result of their excess (Rang et al., 1999). The monoamines involved in depression are noradrenaline and serotonin (5-hydroxytryptamine / 5-HT). Thus pharmacotherapy of affective disorder aims to restore the normal balance of monoamines.
Tricyclic antidepressants (TCAs)
Tricyclic antidepressants (TCAs) such as amitriptyline are the traditional antidepressant drugs. They act by competing with amines and blocking their uptake into the nerve terminal, thus increasing levels in the synapse.
The fact that TCAs are able to block multiple neuro-receptors, influence 2nd messengers and ion channels as well as inhibiting the neurotransmitter reuptake sites (Horst & Preskorn, 1998) means that they have a relatively wide side effect profile. Side effects include dry mouth, blurred vision and constipation (Rang et al., 1999) as well as slowed cardiac conduction due to sodium channel inhibition (Horst & Preskorn, 1998).
It has also been noted that, whilst rare, mania can result from sudden withdrawal of TCAs, even in cases when they were being used to treat unipolar depression (Ali & Milev, 2003). Whilst it is unclear why this occurs, it has been suggested that it might relate to a relative monoamine excess.
5-HT uptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) were developed to overcome the side effects observed in TCA treatment. They act solely to reduce the reuptake of serotonin into nerve terminals; increasing neurotransmitter levels and reversing the functional deficit. Figure 1 below shows the normal activity at the synapse, and the effect of SSRIs.
SSRIs are effective in treating mild depression but not severe depression (Rang et al., 1999) and do not have the wide spectrum of activity of TCAs (Horst & Preskorn, 1998) thus don’t share the same side effects.
The most well known SSRI fluoxetine prozac is widely prescribed and acts by binding to the carrier protein responsible for the uptake of serotonin, leading to that protein not being able bind to the serotonin and transport it across the nerve synapse (Patrick, 2001). Fluoxetine is believed to be associated with reduced manic induction in bipolar patients (Amsterdam & Shults, 2005).
A significant disadvantage of SSRIs is the 2-3 week latency before they begin to have their antidepressant effect. This is believed to result due to the initial decrease in serotonergic neuron firing caused by accumulated 5-HT acting on the inhibitory 5HT1A receptors in the dorsal raphe nucleus (Plenge & Mellerup, 2003). However, with continued SSRI administration these autoreceptors become desensitised and overall 5-HT transmission can be enhanced. Newer drug therapy aims at co-administration of 5HT1A antagonists with SSRIs to prevent the autoreceptor mediated latency in desired action. One such drug is pinodol, which, whilst primarily a (-adrenergic antagonist, also acts on the 5HT1A receptors and has been shown to be effective in conjunction with SSRIs such as paroxetine (Plenge & Mellerup, 2003).
Monoamine oxidase inhibitors (MAOI)
Monoamine oxidase (MAO) is the enzyme responsible for removing monoamines such as dopamine and serotonin from the synaptic end plate. MAOI such as iproniazid and selegiline act by covalent binding to MAO and causing a long lasting inhibition of its activity at the synaptic plate (Rang et al., 1999).
Whilst MAOI reliably increase monoamine levels they are associated with severe side effects, in which foods such as cheese and nuts containing pressors will result in a severe sympathetic reaction. This is caused by the systemic inhibition of MAO, resulting in the catecholamine like pressors having a sustained and dangerous hypertensive effect (Carlson, 2001; Rang et al., 1999).
Atypical antidepressants
Atypical antidepressants are thus called as they do not act in the same way as TCAs, MAOIs or SSRIs. Atypical antidepressants include bupropion, venlaflaxine and nefazodone (Horst & Preskorn, 1998); as well as maprotiline, mianserin and trazodone (Rang et al., 1999). As would be expected the mechanisms of action of atypical antidepressants varies but includes dopamine uptake inhibition as well as increased noradrenaline release and weak activity on other monoamine binding sites (Horst & Preskorn, 1998; Rang et al., 1999). They may also act indirectly via such mechanisms as blocking (2-adrenoceptors leading to reduced inhibitory feedback control (Rang et al., 1999). In general atypical antidepressants achieve similar effects as TCAs and SSRIs but do not act on neuro-receptors, so do not influence cholinergic, histaminergic or adrenergic receptors either at all or to a physiologically relevant degree (Horst & Preskorn, 1998).
Lithium
Lithium has been the mainstay of treatment for bipolar disorder for nearly 50 years (Vieta & Goikolea, 2005) and acts to control the manic phase (Rang et al., 1999). Lithium is effective very rapidly, and acts to remove the mania phase, which prevents the following depressive phase (Carlson, 2001). Lithium is particularly useful as a prophylactic to control and stabilise mood overall in manic depressive illness (Rang et al., 1999).
Lithium acts by accumulating inside excitable cells and causing depolarisation via partial loss of intracellular potassium (Rang et al., 1999), thus preventing excessive action potentials. In addition lithium acts on intracellular 2nd messenger systems, which also results in reduced action potential generation over time. The overall effect of lithium is to reduce the extreme mania observed in bipolar disorder. Unfortunately lithium has a narrow therapeutic range (Rang et al., 1999) and is highly toxic in overdose, thus newer studies suggest drugs such as atypical antipsychotics including olanzapine, which has been found to be more effective than lithium at preventing manic relapse (Vieta & Goikolea, 2005).
Conclusion
It has long been suggested that not all cases of affective disorders arise due to the same underlying biological cause (Horst & Preskorn, 1998), so it is logical that different individuals will respond differently to a variety of drugs. It is also entirely logical that side effects such as weight gain and sexual dysfunction, common side effects of traditional antidepressant medication (Millan, 2004) will reduce patient compliance, leading to poor control of the illnesses.
However, until new specifically targeted drugs are developed, those that target the monoamine system are the current drugs of choice to effectively control affective disorders.
References
Ali, S., & Milev, R. (2003). Switch to mania upon discontinuation of antidepressants in patients with mood disorders: A review of the literature. Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie, 48(4), 258-264.
Amsterdam, J. D., & Shults, J. (2005). Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression–lack of manic induction. Journal of Affective Disorders, 87(1), 121-130.
Carlson, N. (2001). Schizophrenia and the affective disorders. Physiology of behaviour (7th ed.) (pp. 527-556). Boston: Allyn and Bacon.
Horst, W. D., & Preskorn, S. H. (1998). Mechanisms of action and clinical characteristics of three atypical antidepressants: Venlafaxine, nefazodone, bupropion. Journal of Affective Disorders, 51(3), 237-254.
Millan, M. J. (2004). The role of monoamines in the actions of established and “novel” antidepressant agents: A critical review. European Journal of Pharmacology, 500(1-3), 371-384.
Patrick, G. L. (2001). Protein structure. In G. L. Patrick (Ed.), An introduction to medicinal chemistry (2nd ed.) (pp. 20-36). Oxford: Oxford University Press.
Plenge, P., & Mellerup, E. T. (2003). Pindolol and the acceleration of the antidepressant response. Journal of Affective Disorders, 75(3), 285-289.
Rang, H. P., Dale, M. M., & Ritter, J. M. (1999). Drugs used in affective disorders. In H. P. Rang, M. M. Dale & J. M. Ritter (Eds.), Pharmacology (Fourth ed.) (pp. 550-565). Edinburgh: Churchill Livingstone.
Stahl, S. M. (1998). Mechanism of action of serotonin selective reuptake inhibitors: Serotonin receptors and pathways mediate therapeutic effects and side effects. Journal of Affective Disorders, 51(3), 215-235.
Vieta, E., & Goikolea, J. M. (2005). Atypical antipsychotics: Newer options for mania and maintenance therapy. Bipolar Disorders, 7 Suppl 4, 21-33.
Tags: antidepressants, Bipolar disorder, depression, disorders, drug treatment, inhibitors, mania, mood changes, TCAs
