Possible pharmacological properties of antidepressants.
1.Introduction
Depression is one of the most common psychiatric disorders with a life time prevalence of 10% - 20% in the general population and women being at twice the risk of developing depression compared to men (Kessler et al., 2007). Literature suggests that prevalence of depression is higher in patients with chronic illnesses (Katon 2003). It is estimated that around 11%-15% of patients with diabetes, 15%-23% of patients with coronary artery disease, and 9%-31% of stroke patients suffer from depression. The prevalence of depression has been reported even higher among patients with chronic neurological illness such as parkinson’s disease (20%-30%) and multiple sclerosis (16%- 30%).
The high prevalence of depression in the general population has an adverse impact on the community and depression affects the patients well being and their productivity in life. It is reported as the third leading cause of disability as measured by disability adjusted life years (DALYs) and is projected to became the second leading cause in 2020 (WHO 2012). Furthermore, the life time risk of suicide in patients diagnosed with depression is as high as 6% (Inskip et al., 1998).Therefore effective treatment of depression is very important to prevent disability.
The management of depressive disorder is challenging for most clinicians. Over the last 50 years, repeated attempts were made to develop a novel antidepressant, with the intention of maximising the efficacy and minimising the side-effect profile. The research has moved from time to time as in the beginning it was focussed on noradrenaline neurotransmission, later on serotonin neurotransmission. In the last decade, it has moved towards dual action and receptor specific agents. In this chapter we review and update the high quality evidence for pharmacotherapies of depressive disorder and highlight the future trends in the development of new promising antidepressants.
2. Evolution of pharmacotherapy for depression
In 1957, the antidepressant property of isoniazid was discovered serendipitously and this has led the pharmacological research to develop drugs which inhibit monoamine oxidase and drugs which block the reuptake of noradrenaline. This resulted in the development of various monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants (TCA) which dominated the treatment of depression for over 30 years, predominantly TCA’s. In the 1990’s selective serotonin reuptake inhibitors (SSRI) were introduced and quickly they became the first line of treatment for depression. These agents were reported equally efficacious with less side-effects and are safer in overdoses. Over the last decade the research was focussed to enhance the efficacy, accelerate the onset of action and reduce the side- effects. In this regard, many newer agents were introduced with different mechanisms of action and proved very helpful in many aspects. They include noradrenaline reuptake inhibitors (NARI), serotonin and noradrenaline reuptake inhibitors (SNRI), noradrenergic and specific serotonergic antidepressant (NaSSA) and more recently agomelatine.
The combination of SSRI with another newer antidepressant has proved very effective for treatment resistant depression (Blier et al., 2010). RCTs have shown superior effectiveness for combination of antidepressant and psychological intervention (cognitive behavioural therapy) compared to psychotherapy alone (Cuijpers et al., 2009). In addition, studies have confirmed the usefulness of long term antidepressant treatment to prevent further relapses (Nierenberg et al., 2003).
The mechanism of action of currently available antidepressants is mostly monoamine based. Their efficacy is relatively modest and the benefits may be limited by poor tolerability. This has led research to search for antidepressants with different mechanisms of action including multimodal serotonergic agents, triple uptake inhibitors, neurokinin based drugs and glutamate based agents.
3. Monoamine hypothesis of depression
The monoamine hypothesis remains the main aetiological theory of depression. It suggests that depression occurs as a result of an abnormality in the monoamine neurotransmitter system in the brain. The monoamines involved are serotonin, noradrenaline and dopamine.
Numerous abnormalities in the monoamine system have been linked with depressive symptoms in patients suffering major depression. The earliest evidence came from the observation that reserpine causes depletion of monoamines and induces a state similar to depression (Healy & Savage 1998). Studies have reported abnormalities in the metabolism of these neurotransmitters as well as changes in the neuroendocrine measures which are affected by these monoamines. These include decreased plasma tryptophan levels, a precursor of serotonin, noted in untreated depressed patients (Anderson et al., 1990) and low cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the metabolite of serotonin, found in depressed patients who attempted suicide (Brown and Linnoila 1990). Furthermore, depletion of serotonin or noradrenaline in patients who were recovered from their depressive episode made them more vulnerable to relapses (Smith et al., 1997; Berman et al., 1999).
Monoamine theory has been supported by the receptor changes that occur during treatment with antidepressant medications whose main mechanisms of action are to either increase the synaptic levels of monoamines or to have an effect on post-synaptic receptors. Initially due to low levels of neurotransmitters, the post-synaptic receptors become supersensitive. On antidepressant treatment, the levels of neurotransmitters are increased and the receptors go into a persistent activated mode. This may be a cause of delay in the onset of action of antidepressants. During the long term treatment, the alpha- 2 auto receptors in noradrenergic system become desensitized resulting in additional release of noradrenaline from the neurons. Further studies have helped to recognise the different roles of various monoamine receptors and the effects of the drugs acting on these receptors.
The possible pharmacological properties of the antidepressants acting via neurotransmitters on the various receptors are shown in Table 1.
|
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Inhibition of MAO Inhibition of NA re-uptake Inhibition of 5HT re-uptake |
Alleviation of depression Alleviation of depression Alleviation of depression Sexual dysfunction, anorexia, gastro-intestinal distress, headache, dizziness |
Activation of 5HT1a receptors | Alleviation of depression |
Antagonism of 5HT2 receptors | Alleviation of depression, weight gain |
Antagonism of 5HT3 receptors | Alleviation of anxiety and psychotic symptoms |
Activation of 5HT3 receptors | Nausea/ vomiting |
Antagonism at H1 receptors | Potentiation of central depressant drugs, sedation, drowsiness, confusion |
Antagonism at muscarnic receptors | Blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, confusion |
Antagonism at alpha 1 receptors | Postural hypotension, dizziness, reflex tachycardia, sedation, drowsiness |
Antagonism at alpha 2 receptors | Alleviation of depression |
4. Increasing synaptic levels of monoamines
4.1. Tricyclic Antidepressants (TCA)
Tricyclics increase the levels of monoamine neurotransmitters in the synapse by inhibiting re-uptake of both serotonin and noradrenaline back into the pre-synaptic neurons. They also act on various other receptors including cholinergic and histaminergic receptors which relate to their side-effects. They have cardiac membrane stabilising action which can cause arrthymias and heart blocks. The use of TCAs has declined over time due to poor tolerability and high toxicity in overdoses, particularly cardiac side-effects. Repeated attempts to modify this side-effect has led to the development of Lofepramine, a relatively new TCA which has less cardiac side-effects and seems to be safer in overdose, while its efficacy remains similar to that of other tricyclics. There is good evidence that TCAs are more effective in severe depression, particularly inpatients compared to SSRI’s (Geddes et al., 2002) and a small number of TCA’s are still used in clinical practice.
4.2. Monoamine Oxidase Inhibitors (Irreversible MAOI)
Traditional MAOIs increase the levels of neurotransmitters by irreversibly blocking monoamine oxidase enzymes in the synapse and the enzyme blockade lasts for two weeks even after stopping MAOI. They block both MAO-A and MAO-B enzymes, not only in the nervous system but also in the gut. As a result, they have a dangerous interaction with tyramine containing foods and sympathomimetic drugs causing a hypertensive crisis. This restricts patients from consuming tyramine containing foods and certain other medications such as cold remedies and cough suppressants.
MAOIs are now used as third line drug in the treatment of depression due to these limitations. They are very useful in patients who do not respond to SSRI and TCA. It is also useful in atypical depression (depression characterised by mood changes, increased sleep and appetite, weight gain and sensitivity to rejection) and in phobic anxiety disorders. A recent review concluded that MAOI,
4.3. Reversible inhibitor of monoamine oxidase –Type A (RIMA)
These new generation MAOIs are more selective in their action, in that they block only MAO-A not MAO-B enzymes. The inhibition is reversible and it doesn’t require the lengthy wash-out periods after stopping them. The efficacy of
5. Selective Serotonin Reuptake Inhibitors (SSRI)
The discovery of SSRIs in 1989 was a turning point in the treatment of depression. It switched the emphasis from noradrenergic to serotonergic system and stimulated research on serotonin receptors. SSRIs are more selective in inhibiting only serotonin reuptake and have no action on histamine, adrenaline and cholinergic receptors. Therefore their tolerability is much better compared to TCAs or MAOIs. They have similar efficacy to older drugs, but better tolerability and safety in overdoses and have become the first line of treatment for depression over the last two decades. There are six drugs available in this group namely
Although these six medications differ in their chemical structure and pharmacokinetics (Van Harten 1993), there are no major differences in their efficacy or side-effect profile (Aguglia et al., 1993). The common side-effects include gastro-intestinal problems, dry mouth, sweating, headache, asthenia and sexual dysfunction such as ejaculatory delay/failure and anorgasmia. SSRIs have fewer drug interactions compared to older drugs and the most important one is with MAOI when concurrent administration may cause serotonin syndrome. Therefore MAOIs and RIMA are contraindicated in combination with SSRIs and there should be a washout period before swapping them.
The safety profile of these drugs was found to be similar (Price et al., 1996) and they do not cause physical dependence. However, abrupt withdrawal or marked reduction in the dose of SSRI may lead to the development of discontinuation symptoms. The common symptoms are dizziness, paraesthesia, tremors, anxiety, nausea and increased heart rate which may last for up to 10 days. Paroxetine causes discontinuation symptoms more often (5.1%) than other SSRIs (0.06- 0.9%).
6. Serotonin Antagonist and Reuptake Inhibitors (SARI)
7. Noradrenaline Reuptake Inhibitors (NARI)
Reboxetine is equally effective as TCAs in both hospital patients and outpatients (Berzewski et al., 1997; Dubini et al., 1997) and has better efficacy than fluoxetine. It also helps in alleviating anxiety symptoms associated with depression. It has moderately alerting effect and improves the motivation of the patients. The main side-effects are linked to sympathetic overstimulation and include dry mouth, insomnia, sweating, tachycardia, vertigo, urinary hesitancy and impotence. The daily dose range is 4-12mgs.
8. Selective Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
SNRIs have dual action and inhibit both serotonin and noradrenaline reuptake. They do not act on muscarnic, histaminic or adrenergic receptors. As a result they have more benefits and less side -effects compared to other antidepressants. Venlafaxine, duloxetine and milnacipran belong to this group.
9. Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)
Mirtazapine has a more rapid onset of action (Thase et al., 2010) and is equally effective as SSRIs (Papakostas et al., 2008). It also showed higher remission rates compared to SSRIs. Its side-effects are relatively mild and transient.
10. Dopamine and Noradrenaline Reuptake Inhibitors (DNRI)
Bupropion was found to be as equally effective and tolerable as SSRIs (Thase et al., 2005). It may be beneficial for patients with symptoms of sleepiness, fatigue, low energy, anhedonia and loss of interest (Papakostas et al., 2006; Nutt et al., 2007).
11. Serotonin reuptake inhibitor and 5HT1a receptor partial agonists
12. Melatonin based therapy –Agomelatine
In the last decade, advances in the understanding of the pathophysiology of depression including genetic, neurobiological and neuroimaging studies shifted the focus of research from the monoamines to different theories of depression. One of them assumes that disturbances in the circadian rhythms may play a significant role in the pathogenesis of depression.
The links between circadian disturbances and symptoms of depression such as delay in sleep onset, early morning wakening, fatigue during the day, blunting of normal peaks in subjective energy, mood and alertness are very strong (Germainand Kupfer 2008). Circadian disturbances affect the secretory rhythms of various neuroendocrine hormones such as melatonin, cortisol and noradrenaline. There are also changes in the diurnal variations of core body temperature and plasma cortisol levels. If this internal system desynchronises, the timing of various circadian rhythms is out of phase resulting in depressed mood, sleep changes and impaired neurocognition (Czeisler et al., 2005). Therefore any treatments of depression focusing on circadian rhythm not only restore the sleep-wake cycle but also will have substantial improvements in mood, cognition and day-time fatigue (Hickie & Davenport, 1999).
Melatonin is a hormone naturally secreted by the pineal gland in the body. Its secretion is usually high at night time in normal individuals. It has an important role in the regulation of circadian timing systems by binding to melatonin receptors (MT1 and MT2) in the brain (Weaver 1999). Based on this idea, melatonin based therapies have been developed recently for the treatment of depression.
13. Combination treatments for treatment resistant depression
Although the newer antidepressants have better efficacy in the treatment of depression, nearly one third of patients fail to achieve remission. Moreover complete remission is not always possible and partially treated patients are at higher risk of relapse, experience more personal and socioeconomic problems and have poor quality of life. A patient is considered to suffer treatment resistant depression (TRD) if they fail to achieve remission with adequate trials of two different classes of antidepressants. There are few strategies available to tackle treatment resistance including both pharmacological and non-pharmacological therapies.
The
14. Advances in non-pharmacological treatments of depression
Psychological therapies and physical (non- pharmacological) treatments have been developed and refined in the last few decades. In this section, the evidence of their efficacy in the treatment of depression will be reviewed.
14.1. Psychological interventions
Many psychological interventions have been used in the treatment of depression. These include supportive counselling, cognitive – behavioural therapy (CBT), interpersonal psychotherapy (IPT), mindfulness- based cognitive therapy, problem solving therapy and long term psychodynamic psychotherapy. However, only CBT and IPT have good quality evidence in the treatment of depression either as monotherapy or in combination with antidepressants (Sagar et al., 2009).
CBT has good efficacy in both achieving remission and reducing the risk of recurrence of depression (Vittengl et al., 2009; Hollon et al., 2005). Combination of CBT and antidepressant is more effective than CBT alone (Cuijpers et al., 2009). Therefore current treatment guidelines recommend combing CBT with antidepressant in partial remissions or treatment resistant patients. CBT can also be implemented in different ways such as internet based CBT, self-help guidebooks or even telephone CBT which can be helpful in primary care (Kessler et al., 2009; Simon et al., 2009).
14.2. Physical treatments
Physical treatments for depression have been increasingly acknowledged in recent years. They include electro- convulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation, magneto-convulsive therapy and vagus nerve stimulation.
In deep brain stimulation, electrodes are implanted in the brain and controlled by the internal pulse generator. The stimulation modulates the neurotransmission in the cortico –striatal – thalamic- cortical circuit. It is a reversible procedure and the stimulation can be adjusted according to the patient’s needs (Giacobbe et al., 2006).
Magneto-convulsive therapy is another experimental treatment where seizures are induced by repetitive-TMS in a controlled way targeting the brain structures essential for treatment response, particularly the temporal lobes.
In vagus nerve stimulation, bipolar electrodes are attached to the left cervical vagus nerve and stimulation periods are controlled. The side-effects include hoarseness of voice, pain, cough and dysphagia.
15. The future of pharmacotherapy of depression
Despite the advances in the treatment of depression, the efficacy of currently available antidepressants is still relatively modest and there are patients who do not respond to them. The limitations of the monoamine based antidepressants include slow onset of action, poor impact on certain symptoms such as disturbed sleep and fatigue and they cause multiple side-effects. Numerous innovative approaches have been studied looking at new and different mechanisms for the treatment of depression. Some of these promising approaches are discussed below.
15.1. Selective versus multi–transmitter antidepressants
It has always been a debate whether selective neurotransmission is better than multiple neurotransmission. This issue of selectivity versus efficacy has re-emerged as the newer antidepressants are less selective than SSRIs but relatively more selective than the TCAs.
Burke (2004) reviewed the topic comparing SSRIs against TCAs and somewhat more selective venlafaxine. The review concluded that SSRIs’ success is presumably not because of their efficacy, but rather to ease of use, minimal need for titration, better tolerability and improved safety in overdose. The difference in tolerability is due to the fact that TCAs act on multiple receptors causing more adverse effects. In comparing SSRIs with venlafaxine, Thase et al., 2001 found that venlafaxine had higher remission rates and they attributed this to its “dual action”. However venlafaxine does not have substantial effects on noradrenaline until the dose is increased above 150mgs/day and therefore technically it cannot be considered as a dual acting agent at lower doses.
Perhaps a better way to increase the efficacy is to target the specific receptor rather than increasing overall neurotransmission. If a drug acts only at the specific receptor and alleviates the depressive symptoms then its unnecessary action at other receptors can be avoided. Therefore more receptor specific drugs have to be designed rather than those aiming at greater than previous neurotransmission.
15.2. Other agents in development
The other approach to address the issue of efficacy is developing new agents. The agents in development include multimodal serotonergic agents, triple uptake inhibitors, neurokinin (NK1) antagonists, glutamate antagonists, dopamine agonists and antiglucocorticoid agents.
Biological studies of depression have shown that the secretion of hypothalamic neuropeptides such as corticotrophin releasing hormone (CRH) and vasopressin is elevated in depressed patients. CRH acting through CRH1 receptor may cause symptoms of depression. Depressed patients also have increased cortisol levels which might be responsible for psychotic symptoms of depression. A review of the hypothesis that
16. Conclusions
Major depressive disorder is a complex psychiatric condition, with multiple aetiological factors. The pathophysiology of depression is still evolving with ongoing molecular, genetic and neuroimaging studies. Evidence from neurobiological studies indicates that monoamine hypothesis of depression cannot fully explain the causation of depression. Further research into the aetiology of depression beyond monoamine hypothesis may provide new directions in developing novel agents in the treatment of major depressive disorder.
The initial focus on increasing the synaptic levels of neurotransmitters, especially serotonin and noradrenaline, has already shifted towards dual action and receptor specific antidepressants. Although there have been considerable advances in the treatment of depression since TCAs were discovered in the 1950’s, the current treatments are not fully satisfactory for either patients or clinicians. Research evidence on several new pharmacological and non-pharmacological interventions is still preliminary and further studies are needed to prove their actual benefits.
Acknowledgements
We would like to thank Mrs Jean Kenning for her secretarial support in the preparation of the manuscript.
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