International Journal of Psychiatry in Clinical Practice

ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20

Antidepressants: pharmacological profile and clinical consequences Juan Gibert Rahola To cite this article: Juan Gibert Rahola (2001) Antidepressants: pharmacological profile and clinical consequences, International Journal of Psychiatry in Clinical Practice, 5:1, 19-28 To link to this article: http://dx.doi.org/10.1080/153-136515001300224854

Published online: 12 Jul 2009.

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2001 Martin Dunitz Ltd

International Journal of Psychiatry in Clinical Practice 2001 Volume 5 Suppl 1 Pages S19 ± S28

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Antidepressants: pharmacological profile and clinical consequences JUAN GIBERT RAHOLA

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Unidad de NeuropsicofarmacologõÂ a Facultad de Medicina, Cadiz, Spain

Correspondence Address Professor J Gibert Rahola, Departamento de Neurociencias, Facultad de medicina, Pza Fragela n8 9, 11003, Cadiz, Spain Tel: 00 34 956015225 Fax: 00 34 956015225 E-mail: [email protected]

Three neurotransmitter systems are implicated in the biological basis of depression: the serotonergic system is thought to be a major component in the development of depression and in the efficacy of antidepressant drugs, while the noradrenergic and dopaminergic systems play lesser roles, but are important in the development of antidepressant side-effects. Selective serotonin re-uptake inhibitors (SSRIs) are still the drug treatments of choice in major depressive disorder, but each has a subtly different pharmacological profile, which has implications for pharmacodynamic actions and clinical efficacy and side-effect profiles. Although the precise mechanisms responsible for specific depressive symptoms are not yet well defined, evidence is emerging that some SSRIs may be more effective in combating certain symptoms than others. Fluoxetine appears to be particularly effective in overcoming symptoms of fatigue and low energy, whereas paroxetine or sertraline may be more appropriately used for depressed patients experiencing anxiety. A growing understanding of molecular mechanisms in depression and the unique clinical consequences of each pharmacological agent brings us one step closer to being able to individualize antidepressant treatment on the basis of core presenting symptoms and the needs of the individual patient. (Int J Psych Clin Pract 2001; 5 (Suppl 1): S19 ± S28) Keywords antidepressants fluoxetine fatigue

INTRODUCTION

T

he prescribing physician now has a baffling choice to make in the pharmacological treatment of depression. The advent of the tricyclic antidepressants and the monoamine oxidase inhibitors, which were discovered serendipitously in the 1950s, revolutionized the treatment of depression but gave physicians their first taste of the difficulties associated with matching the right antidepressant to the right patient. Today, more than two dozen agents are available, working through over six pharmacological mechanisms on three key neurotransmitter systems, and the correct choice of treatment for each individual patient has never been more difficult. As our understanding of the biological basis of depression moves beyond the receptor and probes deeper into the complexities of intracellular mechanisms, so too does our realization that each antidepressant agent presents a subtly different

pharmacology low energy major depression

pharmacological profile both at the level of the receptor and within the cell. Progress in understanding these subtle pharmacological nuances is, however, being matched in the clinic by significant developments in understanding individual patient profiles and in differentiating and recognizing the core symptoms of depression. Many believe that we are now entering a new era in the management of depression in which the unique pharmacological aspects of our current treatments and their unique clinical consequences can be matched more precisely than ever with the unique symptom profiles of each of our patients. The selection of antidepressant agent on the basis of the most prominent presenting symptoms and the relative efficacy of each available drug against those symptoms may now be a possibility. This bodes well for the future treatment of our patients with depression and should ensure that the right patient gets the right treatment at the right dose at the right time.

Drowsiness Weight gain Hypotension Constipation Blurred vision Dry mouth Drowsiness Urinary retention Cognitive dysfunction Agitation Psychosis Dry mouth Tremors Tachycardia Erectile and ejaculatory dysfunction Insomnia Anxiety Mydriasis Hypertension Agitation Somnolence Akathisia Asthenia Anxiety Palinopsia Panic attacks Insomnia Sexual dysfunction Weight loss Not clearly related sideeffects Type of side-effect

Nausea Vomiting Headache

Anticholinergic side-effects Alleviation of depression Antiparkinson activity Alleviation of depression Alleviation of depression and anxiety Clinically relevant effects

Sleep restoring Serotonergic alleviation of side-effects depression and anxiety. No sexual dysfunction

H1 blockade M1 blockade D2 stimulation 5-HT3 stimulation a, b activation 5-HT1 stimulation 5-HT2 stimulation 5-HT2 blockade Receptor action

Histamine Acetylcholine Dopamine Noradrenaline Serotonin Neurotransmitter

Two early observations suggested the importance of monoamines (noradrenaline and serotonin) in the pathophysiology and treatment of depression. First was the observation that reserpine, an agent that decreases the availability of both noradrenaline and serotonin in the central nervous system, precipitated depression in a small proportion of people using the drug for the treatment of hypertension.1 The second was the observation that most antidepressant drugs, including tricyclics and monoamine oxidase inhibitors (MAOIs), enhanced the synaptic availability of noradrenaline, dopamine, or serotonin.2 ± 4 A generation of research subsequently followed these early observations in an attempt to establish possible mediators of this antidepressant action. Extensive work evaluating the presynaptic release of monoamines, intrasynaptic or intracellular degradation, receptor binding and modulation has, however, failed to establish a consistent basis for antidepressant effects.5 Studies looking beyond cell surface receptors to transduction cascades and gene expression may ultimately explain any common mechanisms of action of antidepressants, and significant progress in that direction has been made in recent years.5 Nevertheless, the monoamine hypothesis of depression is an enduring one, and the importance of monoaminergic mechanisms in the biopathology of depression continues to be reinforced. 6 ± 8 The differential efficacy of antidepressant drugs can at least partially be explained by their relative receptor binding profiles, and our ability to understand the clinical consequences of each agent is still based primarily on our understanding of the receptor pharmacology of these agents. Three neurotransmitter systems appear to be involved in the biochemical basis of depression: the serotonergic system is well understood and is thought to be a major component in the development of depression and in the efficacy of antidepressant drugs, while the noradrenergic and dopaminergic systems play lesser roles, but are especially important in the development of antidepressant side-effects (Table 1). The monamine hypothesis, put simply, proposes that depression is due to a central deficiency in the neurotransmitters serotonin, noradrenaline or dopamine.9 Serotonin deficiency syndromes are associated with symptoms such as depressed mood, anxiety, panic and phobia, and pharmacological treatment strategies aim to normalize the levels of serotonin available at the synapse. 9 Noradrenaline deficiency syndromes produce psychomotor retardation and cognitive impairment, and strategies to enhance the availability of noradrenaline at the receptor have proved to be effective in alleviating these symptoms.10 The role of dopamine deficiency in the pathogenesis of depression is less well defined, although dopamine dysregulation has been demonstrated in bipolar and delusional subgroups of depressed patients.11

Table 1 Neurotransmitter systems and their clinical relevance in the treatment of depression

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BIOLOGICAL BASIS OF DEPRESSION

Antihistaminergic side-effects

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Serotonergic side-effects

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THE SEROTONERGIC SYSTEM Serotonergic pathways project from the raphe nuclei of the mid-brain, pons and medulla and descend to the cerebral cortex, basal ganglia, limbic cortex/hippocampus and hypothalamus. The serotonergic system is thought to control many aspects of mood as well as having a significant effect on sleep, appetite, pain perception, thermal regulation, gut function, sexual function, cognitive function, sensory interpretation and balance (Figure 1).12 At least 14 serotonin receptor subtypes have so far been identified and these are distributed in different densities throughout the peripheral and central nervous system. 13 In the treatment of depression, it is believed that the 5-HT1A receptor subtype, which predominates in the cerebral cortex, limbic system and hippocampus, is primarily responsible for the antidepressant effects of many drug treatments.

THE NORADRENERGIC SYSTEM Noradrenergic pathways project from the locus caeruleus in the dorsal pons and ascend to the frontal/prefrontal cortex, thalamus and hypothalamus and the limbic system.10 The most important pathway with respect to depression is that innervating the prefrontal and frontal regions (Figure 1).13 Five main subtypes of noradrenaline receptors have been identified: a1, a2 , b 1 , b 2 and b 3,10 and it is thought that the b 1 and b 2 receptors in the frontal cortex play the most significant role in depression. 13 In the limbic system, noradrenaline is believed to be responsible for the regulation of motivation, mood, energy levels and emotion.13,14

THE DOPAMINERGIC SYSTEM The central dopaminergic systems are complex, and include the tubero-infundibular pathways, which control the regulation of pituitary hormones such as prolactin, and the mesocortical and mesolimbic systems, which are

Norepinephrine pathways

Tremor (cerebellum)

Depression (frontal b 1) Energy level Agitation Emotions

Limbic

functionally important in psychotic disorders and in the therapeutic effects of neuroleptic drugs.15 Changes in the functional activity of dopaminergic cells in the neostriatum are also responsible for movement disorders such as Parkinsonism and Huntington’s chorea. 15 The dopamine hypothesis of depression arose only indirectly, as a result of studies that showed a modest antidepressant effect of the catecholamine precursor L-dopa, and subsequent studies with dopamine receptor agonists. 11

INTRACELLULAR EVENTS Although the involvement of these three neurotransmitter systems in the biological basis of depression is now well established, complex events beyond the receptor increasingly appear to be important.5,16 Several antidepressant therapies have been shown to have a direct effect on gene expression, and this, in turn, may enhance the synthesis of neurotransmitters and increase the production of important nerve growth factors.5 Brain-derived neurotrophic factor, which is one of several nerve growth factors involved in the development, differentiation and survival of neurons in the brain, is a particular focus of current research, since several studies have demonstrated its antidepressant properties, 17 and others have found that antidepressant drugs increase its expression in the frontal cortex.18 ± 20 If different antidepressant agents can be shown to differentially affect events leading ultimately to gene expression, the quest to understand the precise pharmacodynamic effects of different antidepressant drugs could, eventually, be over.

PHARMACOLOGY AND CLINICAL CONSEQUENCES Antidepressants can be classified into three groups according to their principal mode of action: neurotransmitter reuptake inhibitors, which prevent monoamine uptake at the synaptic cleft; monoamine oxidase inhibitors, which inhibit monoamine degradation; and adrenergic receptor blockers,

Mood (frontal cortex)

Attention (frontal a 2)

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Serotonin pathways

Akathisia/agitation OCD (basal ganglia)

Blood pressure (brainstem)

Heart rate Bladder Sweating (sympathetic and parasympathetic)

Figure 1 Serotonergic and noradrenergic pathways and the ways they might be involved in depression

Insomnia (sleep centres) Anxiety Sexual dysfunction (limbic) Appetite (spinal cord) Bulimia Nausea and vomiting (hypothalamus) (brainstem vomiting centre) GI cramps/Diarrhoea (gut)

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(b) receptor blockade

(a) re-uptake blockade Presynaptic nerve ending

Antidepressant

Neurotransmitter Postsynaptic receptor

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?

?

Antidepressant

Re-uptake pump blocked

Receptor blocked

Figure 2 Possible actions of antidepressants. (a) Inhibition of the neurotransmitter reuptake transporter and (b) blockade of the neurotransmitter receptors 13 Reproduced from Racagni G, Brunello N (1999). Physiology to functionality: the brain and neurotransmitter activity. Int Clin Psychopharmacol 14 (Suppl 1): S3 ± 7.

which disinhibit noradrenaline and serotonin receptors, thus increasing neurotransmission (Figure 2). Re-uptake inhibitors can be further divided into three categories (Table 2): SSRIs, which are selective for serotonin (e.g. fluoxetine), NRIs, which are selective for noradrenaline (e.g. reboxetine) and SNRIs, which inhibit the uptake of both serotonin and noradrenaline (e.g. venlafaxine). The benefits of these treatments for the symptoms of depression are conferred primarily by their ability to stimulate 5-HT1A receptors, while their activity at 5-HT2A, 5-HT2B , 5-HT3, a1, D2, M1 and H1 receptors contribute to their side-effect profiles. 21 In addition, some treatments appear to be more effective in alleviating specific symptoms than others, with fluoxetine, for example, showing substantial and specific benefits when given to treat low energy and fatigue,22 which is a prevalent symptom in

Table 2 Pharmacology of currently available antidepressants 51,52 Adapted from Preskhorn SH (2000). The adverse event profiles of the selective serotonin reuptake inhibitors: relationship to in vitro pharmacology. J Psychiatr Practice 6: 153 ± 7 and Preskhorn SH (2000) The relative adverse event profile of non-SSRI antidepressants: relationship to in vitro pharmacology. J Psychiatr Practice 6: 218 ± 23. Re-uptake inhibition (potency*) Serotonin Noradrenaline Dopamine

Antidepressant Tricyclic antidepressants Imipramine Clomipramine Amitriptyline Dothiepin Selective serotonin re-uptake inhibitors (SSRIs) Fluoxetine Citalopram Fluvoxamine Paroxetine Sertraline Serotonin and noradrenaline re-uptake inhibitors (SNRIs) Venlafaxine

(low doses) (medium doses) (high doses) Noradrenaline re-uptake inhibitors (NRIs) Reboxetine Noradrenaline and dopamine re-uptake inhibitors (NDRIs) Bupropion Serotonin-2 antagonists/ re-uptake inhibitors (SARIs) Mirtazapine Trazodone Nefazodone *( =negligible or absent;

=low;

=moderate;

=high)

H1

Receptor binding affinity* M1 a1 5-HT2

5-HT3

Antidepressant pharmacology and clinical profiles

many patients with depression, and is particularly difficult to treat. The older antidepressants, such as the tricyclics, have a broad pharmacological profile, and are now falling from favour in the modern era, in which drug treatment for depression is increasingly being targeted at specific depressive symptoms and in which agents are selected specifically to enhance efficacy and avoid side-effects. 23, 24

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TRICYCLIC ANTIDEPRESSANTS The tricyclic antidepressants (i.e. imipramine, clomipramine, amitriptyline) all block the re-uptake pumps for both serotonin and noradrenaline (and to a lesser extent, dopamine). 25 In addition, essentially all tricyclic antidepressants have at least three other actions: blockade of cholinergic M1 receptors, blockade of H1 receptors and blockade of a1 adrenergic receptors.25 Whereas inhibition of the serotonin and noradrenaline re-uptake pumps is thought to account for the therapeutic actions of these drugs, the other three pharmacological properties account for their side-effects.

SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS (SSRIs) Selective serotonin re-uptake inhibitors are now the treatment of choice for the pharmacotherapy of depression and related disorders because of their excellent efficacy and tolerability, and their safety in overdose.26 Several studies have shown that patients taking SSRIs are more likely to achieve an adequate dosage and are less likely to discontinue treatment than those treated with tricyclic antidepressants, which means a significant enhancement in figures for patient compliance. 27 The SSRIs have a more selective and potent effect on the reuptake of serotonin than of noradrenaline or dopamine, but each has a subtly different profile and some appear to be more effective in the management of specific depressive symptoms than others.22 Fluoxetine In vitro studies with fluoxetine have shown that it is 100 times more potent at inhibiting the uptake of serotonin than are dopamine or noradrenaline.28 Fluoxetine has only weak affinity for noradrenergic a1 and a2, histamine H1 and H2, and muscarinic and dopaminergic receptors: hence its favourable side-effect profile. 29 Although there is recent evidence that fluoxetine may inhibit noradrenaline uptake,30,31 and may affect dopamine systems by increasing dopamine receptor density, 32 the drug is generally considered to be an SSRI, since this description reflects most accurately its prime mode of action. In clinical trials, fluoxetine has been shown to be as effective as tricyclic antidepressants in the treatment of major depression of all degrees of severity, but it is simpler for patients to use and for physicians to prescribe. 29

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Fluoxetine has proven effectiveness in patients presenting with anxiety, agitation and depressed mood,29 and recent studies have demonstrated its efficacy in overcoming the treatment-refractory symptoms of fatigue and low motivation in many depressed patients.22,33 Fluoxetine lacks the cholinergic, histaminergic and alpha-adrenergic receptor blockade that produces the unwanted side-effects of tricyclics, and the most common side-effects reported with fluoxetine treatment are transient headache and nausea. 29,34 Citalopram Citalopram inhibits serotonin re-uptake 3000 times more than noradrenaline re-uptake and 22 000 times more than dopamine uptake.35 Although accepted as an effective treatment in mild to moderate depression, citalopram may be less effective than tricyclic antidepressants in more severe cases of depression. 36 Despite its selectivity for the serotonergic system, citalopram can cause nausea and somnolence, indicating significant activity at histaminic H1 receptors. 37 Paroxetine While primarily a serotonin re-uptake inhibitor, paroxetine is also a moderate noradrenaline and dopamine reuptake inhibitor. 26 Its efficacy in mild to moderate depression is well established, although it may be less effective than tricyclic antidepressants in severely depressed patients.38 Paroxetine is more likely than other SSRIs to cause anticholinergic symptoms such as drowsiness, dry mouth and constipation through its activity at the M1 receptor. Paroxetine has also been associated with weight gain26 and, much like fluvoxamine, it is more frequently associated with asthenia and nausea than other SSRIs.26 Symptoms arising from the discontinuation of treatment such as akathisia and dystonia are a particular problem with paroxetine, 9,39 and are due primarily to its very short half-life and its powerful anticholinergic activity. 39 Fluvoxamine Fluvoxamine is a moderate inhibitor of serotonin reuptake and has marginal effects on the re-uptake of noradrenaline. Although effective in the treatment of depression, fluvoxamine is associated with asthenia and nausea more often than are most other SSRIs,26 and a higher percentage of patients who were taking fluvoxamine than of patients taking other SSRIs dropped out of clinical trials.34 Sertraline Sertraline is one of the most potent inhibitors of serotonin re-uptake available. 40 In-vitro studies have demonstrated that the drug is 36 times more potent than fluoxetine and 205 times more potent than amitriptyline at blocking the re-uptake of serotonin.41 Although sertraline has weak

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effects on noradrenaline re-uptake, it is a relatively potent inhibitor of dopamine re-uptake, compared with other SSRIs.40 Sertraline’s activity as a dopamine re-uptake inhibitor makes it most suitable for use in melancholic, endogenous or severe depression, 34 in depression associated with Parkinson’s disease and in the depression or the negative symptoms associated with schizophrenia.40 Sideeffects associated with sertraline treatment include nausea and diarrhoea, headache, insomnia and tremor.34 In addition, some studies have suggested a high incidence of sexual dysfunction in men taking it,42 although this has not been found consistently. 34

SEROTONIN AND NORADRENALINE RE-UPTAKE INHIBITORS (SNRIs) The SNRIs form one of the most recently introduced classes of antidepressants, and the first agent to be introduced into clinical practice is venlafaxine. Venlafaxine Venlafaxine was developed in order to retain the noradrenaline and serotonin re-uptake inhibitory properties of the classical tricyclics but reduce their a1, cholinergic and histamine receptor blocking properties.25 Venlafaxine has dose-related degrees of inhibition of serotonin reuptake (most potent and present at low doses), noradrenaline re-uptake (moderate potency and present at higher doses) and dopamine re-uptake (least potent and present only at highest doses). 25 Although venlafaxine is an effective antidepressant, it is not clear if the SNRIs as a class offer advantages over the SSRIs in terms of either efficacy or side-effects. 25 Medium to high doses of venlafaxine, while possibly conferring a more rapid onset of action, are associated with severe insomnia, agitation and nausea, and may cause headache and hypertension.

NORADRENERGIC AND SPECIFIC SEROTONERGIC ANTIDEPRESSANTS Mirtazapine Mirtazapine is an a2-antagonist, and the therapeutic actions of this group are mediated by blocking presynaptic a2 autoreceptors at noradrenergic neurons and a2 heteroreceptors at serotonergic neurons, increasing the release of both noradrenaline and serotonin. Mirtazapine also acts as an antagonist at 5-HT2A and 5-HT3 receptors. The blockade of 5-HT2A receptors theoretically results in the beneficial effects of 5-HT1A stimulation on depression, in order to enhance intracellular production of neurotrophic factors such as brain-derived neurotrophic factor (BDNF).43 The antagonism at 5-HT2A receptors limits sexual side-effects and restores sleep patterns and at 5-HT3 receptors limits gastro-intestinal side-effects. Mirtazapine, however, also has significant activity at H1 receptors and is therefore associated with drowsiness, an increased appetite and weight gain. 43

NORADRENALINE RE-UPTAKE INHIBITORS (NRIs) The noradrenaline re-uptake inhibitors were developed with the aim of increasing the specificity for noradrenaline and/or serotonin transport sites, while minimizing effects on neurotransmitter receptors, either in the brain or in the periphery. 15 The first `modified tricyclic’, maprotiline, showed a high selectivity for the noradrenergic transport site, but was cardiotoxic in overdose and precipitated seizures in patients predisposed to epilepsy. 15 Another NRI, viloxazine, has been available in some countries since 1974; however, its association with severe nausea, vomiting and migraine has limited its use in practice.15 Reboxetine, which is a close analogue of viloxazine, is now the only NRI in use in the treatment of depression. Reboxetine Reboxetine is a relatively new antidepressant and is the first selective, non-tricyclic, noradrenaline re-uptake inhibitor. It appears to be effective in the treatment of severe depression and has a relatively rapid onset of action.44 The most common side-effects of reboxetine in clinical trials were dry mouth, headache, nausea, sweating, constipation and hypotension. 44

NORADRENALINE AND DOPAMINE RE-UPTAKE INHIBITORS (NDRIs) Currently, only one NDRI has a licence for the treatment of depression. Bupropion, which is prescribed almost exclusively in the USA, and only by psychiatrists, is considered to be the prototypical agent of this class of drugs.25 In Europe and outside the USA, bupropion is more commonly used in programmes for stopping smoking. Bupropion Bupropion itself is a weak re-uptake inhibitor for dopamine and weaker still for noradrenaline. However, bupropion’s active metabolite, which concentrates in the brain, is a powerful blocker of noradrenaline and dopamine re-uptake and is responsible for the drug’s antidepressant effects. 25 Bupropion is an effective antidepressant and generally has activating or stimulating properties, but its association with grand mal seizures has limited its use in clinical practice, despite its efficacy and lack of sexual side-effects.

SEROTONIN-2 ANTAGONIST/RE-UPTAKE INHIBITORS (SARIs) Trazodone and nefazodone These are both mild serotonin re-uptake inhibitors and powerful 5-HT2 antagonists. Although a pure 5-HT2 antagonist might be thought to be a cleaner and safer antidepressant, those that have been tested to date actually look less impressive than other antidepressants available. 25 Trazodone and nefazodone are particularly effective in depression associated with anxiety, agitation, sleep dis-

Antidepressant pharmacology and clinical profiles

turbance and insomnia, but excessive blockade of 5-HT2 receptors causes somnolence, asthenia and palinopsia. In addition, the metabolite of trazodone and nefazodone, mCPP, causes dizziness, lightheadedness, insomnia and agitation and nausea. Powerful antagonism of 5-HT2 receptors may also cause negative effects downstream. 25

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IS A DUAL MODE OF ACTION BETTER THAN ONE? There is currently no consensus about whether a drug with a dual mode of action (i.e. one that increases both serotonergic and noradrenergic neurotransmission) is better than one with a single target neurotransmitter system. Although it has been argued that a dual mode of action may be more efficacious in severe, retarded or treatment-resistant depression, there is no consistent evidence to support this. A dual mode of action may, theoretically, shorten the time to onset of antidepressant effects and may confer benefits in severe or melancholic depression, but more research is required in order to confirm this hypothesis. A recent meta-analysis found no evidence to suggest that a dual or triple mechanism of action is more efficacious than a single one,45 and it would be safe to say that the jury is still considering its verdict on this controversial issue. 24

THE RIGHT DRUG, THE RIGHT PATIENT Although no significant controlled clinical studies have been published comparing the efficacy of different

antidepressants in different groups of patients, anecdotal evidence and the pharmacodynamic properties outlined above would suggest that specific symptom profiles may provide some assistance in the selection of antidepressant therapy (Figure 3). Several distinctive types of depressed patients are typically encountered in primary care: most experience low mood and low energy, lethargy, poor motivation and fatigue, while roughly one in five also experience mild to moderate anxiety, worry and insomnia; a similar number report severe anxiety, panic attacks and severe insomnia. 46 Important evidence is now emerging that different subtypes of depressed patients may have different neurotransmitter disturbances, and patients may, therefore, have different responses to treatment, depending on the underlying disturbance and the drug treatment profile. 16

DEPRESSION ASSOCIATED WITH LOW ENERGY AND FATIGUE In at least one third of patients with depression, fatigue and low energy are the core depressive symptoms.46 For these patients, selecting an antidepressant with minimal sedative side-effects and maximal energy-restoring properties would seem logical. 22 A recent meta-analysis of 66 clinical trials found that fluoxetine caused less sedation, compared with placebo, than sertraline, fluvoxamine and paroxetine,47 and other studies have shown that fluoxetine significantly improves motivation and energy during the treatment of depression. 22 Fluoxetine may therefore be the treatment of choice in this highly disabled group of patients.

Major depression

Low mood Lethargy, fatigue Low energy Poor motivation

Fluoxetine 20 mg

Bupropion 300 mg

Mild to moderate anxiety Worry easily overwhelmed Mild to moderate insomnia Low energy, fatigue

SSRIs

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Venlafaxine

SSRIs SNRIs Figure 3 Antidepressant selection on the basis of pharmacodynamic profile and dominant depressive symptoms

Severe anxiety Panic attacks Severe insomnia

Paroxetine Sertraline

Mirtazapine Nefazodone Trazodone

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In patients who have low energy or fatigue associated with their depression, who do not respond to serotonergic boosting by SSRIs as a first-line treatment option, bupropion or reboxetine may be a useful second-line agent because of their CNS-stimulating properties.25,48 Depression associated with mild to moderate anxiety, low energy and fatigue Because many patients with low energy also exhibit concomitant anxiety, a physician may be inclined to prescribe a `sedating antidepressant’. However, in patients already suffering from fatigue and low energy, the risks associated with daytime sedation may be of great concern, and most patients, when questioned, would prefer a drug that caused no daytime drowsiness. 49 All SSRIs that do not display sedative side-effects are suitable for use in this group of patients, and low doses of venlafaxine may also be effective. 50 Depression associated with severe anxiety and panic Due to their combined antidepressant and sedative properties, sertraline and paroxetine, along with the 5-HT2 antagonists, may be the most appropriate drugs to choose in these severely anxious patients.

CONCLUSIONS Our increasing understanding of the biological basis of depression and of the pharmacodynamic profiles of our antidepressant agents is gradually allowing us to fine-tune drug selection on the basis of individual symptom profiles. Fluoxetine shows unequivocal efficacy in the treatment of depression associated with fatigue and low energy, and it may therefore be the treatment of choice in patients reporting these symptoms. While differences in the receptor pharmacology of our currently available antidepressant treatments can, in part, explain differences seen in clinical practice, the secret of their differential clinical consequences probably lies beyond the receptor. The next phase of our journey will take us into the heart of the cell, where transduction cascades and gene expression pathways may help us to explain why some patients with depression experience fatigue while others become anxious, and why some antidepressant agents are more effective than others in resolving these core depressive symptoms.

are known to increase in depression, may play a significant role. Professor Thompson: I was quite surprised to see how many of the SSRIs are also noradrenaline re-uptake inhibitors. How do they compare to venlafaxine in terms of their potency? Professor Gibert Rahola: If we look at fluoxetine 20 mg, we can see it has a dual mechanism of action, whereas venlafaxine 75 mg is only serotonergic. The manufacturers of venlafaxine had to double the dose to 150 mg in order to get the dual mode of action they wanted to market. Professor Demyttenaere: You mentioned that a dual mechanism of action might translate into an earlier onset of action, but you only see that with the high doses of venlafaxine. Professor Thompson: Yes. If you start a patient on venlafaxine 300 mg, you might see an early onset of action, but the drop-outs from treatment are enormous. This makes the early-onset studies with venlafaxine almost uninterpretable. Professor Gibert Rahola: You also get three kinds of sideeffects at this dose of venlafaxine: serotonergic, noradrenergic and dopaminergic. Dr Lecrubier: Although you discussed some theories about molecular mechanisms of depression, we don’t yet have conclusive evidence about what happens beyond the receptor. It is also quite speculative which

KEY POINTS

· · ·

·

DISCUSSION Professor Thompson: What do you think might be the mechanism underlying fatigue and low energy in depression? Professor Gibert Rahola: We don’t know for sure, although neuroimaging studies show a loss of neurons in the hippocampus and prefrontal cortex, especially in melancholic patients. There may be a correlation between cytokines and fatigue, but I think apoptotic factors, which

·

A deficiency of serotonin and noradrenaline is central to the biological basis of depression Antidepressant drugs that enhance the synaptic availability of serotonin and noradrenaline but have low affinity for histaminic or cholinergic receptors provide the most efficacious side-effect profiles Serotonin re-uptake inhibitors (SSRIs) are still considered to be the best first-line agents in the treatment of depression because of their favourable pharmacological profiles; however, each SSRI has different pharmacodynamic properties and some may be more suitable for certain patients than others Patients with major depressive disorder can be classified into several distinct groups according to their core symptoms, and selection of antidepressant agent should be made on the basis of each individual’s symptom profile and the drugs’ pharmacodynamic properties Fatigue and low energy are common core symptoms of major depressive disorder and the SSRI, fluoxetine, appears to be especially effective at restoring energy levels and overcoming fatigue

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Antidepressant pharmacology and clinical profiles

mechanisms confer which clinical benefits in the pharmacological treatment of depression, although the mechanisms associated with drug side-effects are better understood. Professor Thompson: I agree. Although we think that cytokines and endocrinological factors may be involved in the development of depression, these are only speculative mechanisms and we certainly don’t understand the interaction between them. The only mechanisms we really understand with any certainty are the synaptic ones and even those are really quite undifferentiated. If you increase serotonergic function, you are going to increase noradrenergic function and vice versa. I don’t think you can draw a hard line between the SSRIs and the NRIs. Dr Lecrubier: Except of course where you have a syndrome that is induced by 5-HT, such as premenstrual syndromes. Then the benefits you see with the SSRIs are quite logical and straightforward.

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Professor Thompson: Do you think we really can differentiate any of the antidepressants in terms of their effects on specific symptoms? Does anyone, for example, believe that reboxetine has a superior action on social function and energy compared with fluoxetine? Dr Lecrubier: No, there is no evidence for this. Professor Demyttenaere: I agree. I don’t think there is any evidence that an NRI is any better than an SSRI in these domains. Professor Thompson: I think all we can really say is that some of these drugs appear to be more effective in severe depression. In my view, amitriptyline and clomipramine might be superior in severe depression, but these studies are not conclusive. Dr Lecrubier: I think there is evidence that some drugs are more effective in hospitalized patients, but not necessarily in severe depression.

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