The pharmacological treatment of unipolar disorder

Mood disorders, particularly depression, are among the more psychologically plausible of mental health problems. For this reason, the general public assumes that psychotherapeutic approaches are the naturally effective treatment for these conditions. Even after a targeted public campaign (Defeat Depression, Royal Colleges of General Practitioners and Psychiatrists), this belief persists together with the conviction that antidepressants are addictive (Paykel et al., 1998). In contrast to this public belief, the evidence for the efficacy and safety of pharmacotherapy far outstrips that of any psychological treatment. Antidepressants are traditionally divided by chemical and historical criteria into first-generation tricyclic anti-depressants, such as amitriptyline, nortriptyline, imipramine and desipramine, trimipramine and clomipramine; second-generation tricyclics, such as doxepine and dothiepine; serotonin reuptake inhibitors (SRIs), such as citalopram, fluvoxamine, paroxetine and sertraline; nora-drenalin (norepinephrine) reuptake inhibitors, such as reboxetine and maprotiline; and miscellaneous drugs, such as venlafaxine, mianserin, mirtazepine, trazodone, reboxetine and buproprion (see Table 7.1). In addition, there are reversible and irreversible monoamine-oxidase inhibitors, such as moclobemide, and phenelzine and tranylcypromine, respectively. Augmentation strategies (Hawley et al., 2000) and poorly empirically supported therapies, such as polypharmacy, which are nevertheless commonly used. (Frye et al., 2000; Stimpson et al., 2002), have to be left to more specific pharmacological texts. While controlled studies clearly indicate the specific antidepressant effects of many anti-depressants, there is also more indirect secular evidence of a general decline in suicide: 'The risk of suicide in follow-up studies of affective disorder has decreased compared to that reported in previous reviews. The availability of ECT [electroconvulsive treatment] and

Mood Disorders: A Handbook of Science and Practice. Edited by M. Power. © 2004 John Wiley & Sons, Ltd. ISBN 0-470-84390-X.

Table 7.1 Commonly used antidepressants

Class of Monoamine antidepressant affected Mode of action Other notes

Table 7.1 Commonly used antidepressants

Class of Monoamine antidepressant affected Mode of action Other notes

Tricyclic antidepressants

(TCAs)

Noradrenalin (NA) and serotonin (5-HT)

Reuptake inhibition

• Individual TCAs vary in the proportion of NA and 5-HT reuptake

• Larger number of side effects

• May be more effective in severe depression

SRIs

Mainly 5-HT, but can have NA and

Dopamine (DA) effects as well

Reuptake inhibition

• Now used as first-line treatment

• More selective action than TCAs

• Generally fewer side effects than TCAs, and better tolerated

5-HT and NA-RIs (Venlafaxine)

5-HT and NA, at higher doses possibly DA

Reuptake inhibition

• At lower doses, mainly 5-HT action

• At moderate doses, NA action

• Pronounced withdrawal effects

NA-RIs

NA

Reuptake inhibition

• Increased risk of seizures

NA and DA reuptake inhibitor

NA and DA

Reuptake inhibition

• Only licensed in USA

Monoamine oxidase inhibitors

NA and 5-HT and DA

Prevents synaptic breakdown of NA and 5-HT

• Tranycypromine is activating

• Tyramine-low diet required

5-HT2antagonists plus reuptake inhibitors (Trazodone)

5-HT2receptors, less powerful re-uptake inhibition

• Acts both pre- and post-synaptically

• Belief that both components are important for therapeutic effect

Mianserin, Mirtazepin

NA and 5-HT

Blocks pre-synaptic a2-receptors

• Pre-synaptic a2-receptors usually inhibit release of NA and 5-HT

• Blocking these receptors stops the inhibition

Lithium

5-HT and others

• Possibly influences post-synaptic second messenger systems once receptor is activated

antidepressants may have contributed to this decrease, but prescription of these treatments cannot be assumed for all patients'. (O'Leary et al., 2001).

Pharmacological treatments of depression continue to be based on the monoamine hypothesis of depression. In its original form, this stated that 'depression is associated with a central depletion of noradrenaline' (Bunney & Davis, 1965; Schildkraut, 1965). It has since been elaborated to encompass reductions in the other monoamines (serotonin and dopamine) and to postulate alterations in monoamine receptor sensitivities in order to explain the delay of the treatment response (Charney et al., 1990). It developed from the observation that antihypertensive agents, such as reserpine, which deplete neurons of noradrenalin, could trigger depressive symptoms. Because of limited access to the human brain in vivo, the confirmation of this hypothesis has proven difficult. Investigators have used peripheral biological markers, such as serotonin metabolite concentrations in urine and cerebrospinal fluid (CSF) as indices of central monoamine function, sometimes with contradictory results. The introduction of functional neuroimaging techniques for the in vivo examination of receptor systems promises more direct hypothesis testing (Ebmeier & Kronhaus, 2002).

TRICYCLIC ANTIDEPRESSANTS (TCAs)

Since Kuhn first described the use of imipramine in treating depression (Kuhn, 1958), convincing evidence has accumulated to support the effectiveness of TCAs in the acute treatment of depression of moderate to severe severity, in improving both response and recovery. Overall, randomised, controlled trials of acute treatment find that 50-60% of patients respond to antidepressants compared with 25-30% on placebo (Schulberg et al.,

1999). This means that only three to four patients need to be treated with an antidepressant in order for one more patient to respond than on placebo. Tricyclic antidepressants, particularly amitriptyline, thus remain the reference standard for antidepressant therapy (Barbui & Hotopf, 2001). They generally generate more severe side effects, including sedation and, in particular, anticholinergic symptoms, such as dry mouth, blurred vision, constipation and urinary retention. This is associated with reduced acceptability for patients compared with some of the newer drugs (Anderson, 2001; Barbui et al., 2000). There is a hotly disputed conflict between the lower doses used in general practice (100 mg and less of a tricyclic) and the expert opinion that doses above 100 mg are required for optimum response (Furukawa et al., 2002). Tricyclics are now used mainly as second-line treatment after newer drugs have proved ineffective, not least because their cardiac effects render them more dangerous in overdose.

SEROTONIN REUPTAKE INHIBITORS (SRIs)

The attempt to isolate the effective principle of tricyclics and the following effort of diversification and market penetration have, over the past couple of decades, resulted in a whole generation of SRIs. These drugs are generally better tolerated than tricyclics, but have a side-effect profile of their own, including headache, nausea, akathisia and a characteristic withdrawal syndrome that is not, however, associated with behavioural dependence (Haddad, 2001). Certain authors have considered psychomotor restlessness (akathisia) as a side effect of SRIs, along with emergent suicidal thoughts and behaviour, but the evidence accumulated so far is limited and unconvincing (Hansen, 2001). However, adding benzodiazepines to these drugs can increase adherence and effectiveness (Furukawa et al.,

2000). It has long been known that in the course of treatment with any antidepressants there is a vulnerable period when psychomotor retardation and indecision improve at a time when suicidal and depressive symptoms still persist. All practitioners should be aware of this risk and discuss it with staff, relatives and patients as part of the overall management plan, although, as yet, it is not clear which educational or informational interventions are best to achieve adherence and optimise efficacy. (Pampallona et al., 2002). In summary, and comparing SRIs with each other and with other antidepressants, there appears to be 'a slower onset of therapeutic action of fluoxetine over other [S]SRIs; a different side effect profile of [S]SRIs to TCAs with superior general tolerability of [S]SRIs over TCAs; poorer tolerability of fluvoxamine than other [S]SRIs in a within group comparison; [and] no increased the risk of suicidal acts or ideation in fluoxetine compared with TCAs (or placebo) in low-risk patients' (Anderson, 2001).

OTHER ANTIDEPRESSANTS

Other antidepressants share certain behaviours in animal models of depression with the older drugs (which is usually how they have entered clinical trials), but possess a diversity of potential mechanisms of action (Table 7.1). At normal doses, venlafaxine behaves like an SRI, but at higher doses also has noradrenalin reuptake-inhibiting properties. It may be more effective than SRIs, but probably not TCAs. (Anderson, 2001; Smith et al., 2002). Other antidepressants (see above) may have certain advantages in terms of side effects or may be used by the specialist in the course of a systematic trial-and-error procedure to find an effective treatment in treatment-resistant patients. Finally, although the presence of a major depressive episode is a good predictor of treatment response, antidepressants have been used effectively in anxiety disorders and in patients with dysthymia (Lima & Moncrieff, 2000).

L-Tryptophan (Table 7.2) is an essential amino acid and the precursor of serotonin (5-HT), tryptophan-hydroxylation being the rate-limiting step in 5-HT production. Thus, it has been suggested as an adjunct treatment for depression, to be added to a conventional anti-depressant. The rationale is that, with reuptake inhibition, more 5-HT is available for degradation, eventually leading to a central 5-HT deficit state. Some evidence supports this view. In those recovered from depression, the exclusion of tryptophan from the diet and administration of a tryptophan-depleting drink can lead to a rapid resurgence of depressive symptoms (Delgado et al., 1999).

Most pharmacological attention has focused on 5-HT and noradrenalin-augmenting strategies. However, there are a number of lines of evidence to suggest that dopamine function is altered in depression, and that patients may benefit from dopaminergic intervention. In Parkinson's disease, which is associated with dopamine deficiency, up to 40% of patients develop depression (Cummings, 1992). Both parkinsonian and the associated depressive symptoms can be treated with pramipexole, a drug which directly stimulates the dopamine D2 receptors. Interestingly, pramipexole appears to exhibit antidepressant properties also in non-parkinsonian patients (Corrigan et al., 2000). Reduced dopaminergic turnover has been found in depressed patients (Jimerson, 1987), and many antidepressant treatments, including ECT, buproprion and amphetamines, have a direct or indirect effect on dopamine (Diehl & Gershon, 1992). More direct evidence comes from in vivo receptor imaging in depression. Investigators (Ebert et al., 1994; Shah et al., 1997) have found evidence of reduced dopamine D2 receptor occupancy in depressed patients, a feature which was associated with motor slowing.

For many years, it has been recognised that depressive episodes often succeed psychologically or physically stressful events. A large body of evidence suggests that the regulation of 'stress hormones', particularly of cortisol, is abnormal in depression. This has given rise to the glucocorticoid-cascade hypothesis of depression (Sapolsky et al., 1986). In severe depression, cortisol levels are often raised (Carroll et al., 1976). Monoamine systems and cortisol are interdependent, and, at least in animal models, raised cortisol can have neuro-degenerative effects (Sapolsky et al., 1986). An increasing number of studies indicate

Table 7.2 Other agents with possible use in depression

Drug

Possible action

Notes

L-Tryptophan

Increases production

1.

L-tryptophan is a basic amino acid

of 5-HT

found in food

2.

Only L-tryptophan can be converted

to 5-HT

3.

Usually used as an add-on

treatment

Amphetamines

Pre-synaptic dopamine

1.

Addiction potential

Methylphenidate

release

Pramipexole

Dopamine D2 receptor

1.

One randomised control trial of its

agonist

effectiveness in depression

2.

Useful for depression in Parkinson's

disease

Oestrogens

Downregulate 5-HT2

1.

May be a useful adjunct treatment

receptors

in post-menopausal women lacking

oestrogens

Thyroxine

Unclear; possible

1.

Usually used as an adjunct

sensitisation of NA

treatment

receptors

2.

Based on the observation that

hypothyroidism can mimic clinical

depression

3.

20% of depressed patients have

evidence of biochemical thyroid

abnormalities

Antiglucocorticoid

Inhibits the action or

1.

Systematic review indicates positive

drugs

production of cortisol

evidence for antidepressant effect

2.

May influence the reciprocal

cortisol-monoamine systems

Folic acid

May aid neuronal

1.

Recent studies suggest that it may

regeneration

be useful in women with depression

2.

Action remains unclear

structural brain changes in depressed patients (Drevets et al., 1998; Shah et al., 2001; Sheline et al., 1996). If this were the case, drugs which control the production or effect of cortisol could have antidepressant effects. A recent review has suggested that antiglucocor-ticoid drugs have some form of antidepressant effect in about 67-77% of patients, roughly equivalent to the size of response seen with conventional antidepressants (Wolkowitz & Reus, 1999). The best response was observed in depressed, hypercortisolaemic patients, suggesting a causal role for HPA dysfunction in some patients. Preliminary pathological evidence has emerged of neuronal cell loss in the brains of previously depressed patients, in areas innervated by monoamine systems (Rajkowska et al., 1999). The recent finding that many antidepressant treatments, including TCAs, SSRIs, ECT and lithium, promote the production of brain-derived nerve growth factor (BDNF), which may help neuronal regeneration (Vogel, 2000), has made some investigators speculate that some of the therapeutic effects of antidepressants are due to neuroregeneration (Miguel-Hidalgo & Rajkowska, 2002). This may also explain the recent finding of an antidepressant effect of folic acid (Coppen & Bailey, 2000), a substance critical for the growth of healthy neuronal tissue.

ST JOHN'S WORT

St John's wort (Hypericum perforatum), has been used for its therapeutic effects for centuries. Lately, the plant extracts have been increasingly popular as a herbal antidepressant. In many European countries, St John's wort is available on prescription, while in others it is sold as a dietary supplement. In Germany, in fact, St John's wort is the leading treatment for anxiety, and depressive and sleep disorders, and the herb is outselling the standard antidepressant fluoxetine (Prozac) by a factor of four to one (Di Carlo et al., 2001). An increasing number of people self-medicate with various extracts of this plant, so there is an urgent need for information about their exact mechanism of action and about possible side effects and drug interactions. Hypericum extracts available commercially contain a large number of constituents, and it is unknown which is responsible for the antidepressant properties of the herb. Some of the most researched compounds are the napthodiathrones, including hypericin and pseudo-hypericin, and the phloroglucinols, such as hyperforin, tannins and flavinoids. The concentrations of constituents vary among the different extracts due to different plant types, growing conditions, preparations and processing procedures, making it difficult to establish active mechanisms of Hypericum extracts. In the following, we aim to outline the available evidence for an antidepressant action of H. perforatum.

In 1996, Linde et al. published a systematic review and meta-analysis of the evidence of 23 placebo-controlled clinical trials of St John's wort in the British Medical Journal (Linde et al., 1996). Its objective was to establish whether extracts of St John's wort are more effective than placebo in treating depressive disorders, whether the herb is as effective as standard antidepressants, and whether it has fewer side effects. H. perforatum extracts were significantly superior to placebo: 55% of the active treatment group responded to the treatment, compared with only 22% in the placebo group. When Hypericum extracts were compared with standard antidepressants, both treatments showed similar effectiveness, 64% responding to Hypericum compared with 58% receiving standard antidepressant treatment. Hypericum extracts appeared to be better tolerated than treatment with antidepressants; fewer patients in the Hypericum group dropped out due to side effects. Since then, in randomised, double-blind and controlled trials of depression, Hypericum extracts have been found to be as effective as and better tolerated than imipramine (Woelk, 2000) and amitripty-line (Wheatley, 1997). Philipp and colleagues (Philipp et al., 1999) randomised over 250 patients to either 1050 mg Hypericum extract (0.2-0.3% hypericin and pseudo-hypericin and 2-3% hyperforin according to HPLC), 100 mg of imipramine or placebo. Hypericum and imipramine were equally effective, but were better than placebo at 4, 6 and 8 weeks of the trial. The imipramine dose was clearly suboptimal, and Hypericum was prescribed at a higher than usual dose; nevertheless, both treatments were effective. In contrast, a large multicentre study (Hypericum Depression Trial Study Group 2002) could not find a significant difference in efficacy between placebo and St John's wort. Figures 7.1a and 1b illustrate the effect of Hypericum compared with placebo and comparator drugs, respectively. From the variability of the placebo-controlled results (Q-'non-combinability' for risk difference = 123.5, df = 14, P < 0.0001), it appears that study outcomes are significantly diverse due to design, drug composition or patient selection, so that results cannot be pooled.

One of the possible impediments to optimising the efficacy of Hypericum studies is that the active principle has not yet been identified (Chatterjee et al., 1998, 2001; Muller et al., 1997, 1998; Singer et al., 1999). Although this may go against the principles of some of

Schlich 1987 Schmidt 1989 Halama 1991 Osterheider 1992 Reh 1992 Konig 1993 Lehrl 1993 Quandt1993 Schmidt 1993 Sommer1994 Hansgen 1994 Hubner 1994 Philipp 1999 Keller2001 JAMA 2002

DL pooled risk difference = 0.28847 (95% CI = 0.156013 to 0.420926)

Figure 7.1a Comparison of St John's wort with placebo—proportion of patients improved after St John's wort minus those improved after placebo (risk difference). Data previous to 1997 cited from (Linde et al., 1996). Computation and graphics were done with StatsDirect, Version 1.9.15, May 2002

its proponents, only detailed analysis of its components' antidepressant actions will make Hypericum a reliably effective and acceptable antidepressant.

Getting to Know Anxiety

Getting to Know Anxiety

Stop Letting Anxiety Rule Your Life And Take Back The Control You Desire Right Now! You don't have to keep letting your anxiety disorder run your life. You can take back your inner power and change your life for the better starting today! In order to have control of a thing, you first must understand it. And that is what this handy little guide will help you do. Understand this illness for what it is. And, what it isn't.

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