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Depression Homeopathic Treatment

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Figure 7.4. Summary of the site of action of mirtazepine (NaSSA). The inhibitory a2 adrenoceptors facilitate the release of both noradrenaline and serotonin (via the heteroceptor on the 5-HT neuron). This is further enhanced by the aj receptor on the serotonin cell body. Thus mirtazepine (and to a lesser extent mianserin) enhance both noradrenergic and serotonergic ^

transmission. ^

Herbal antidepressants - St John's Wort (Hypericum officinalis)

St John's Wort in recent years has become widely used in Europe and North America for the treatment of mild depression. Unlike all other antidepressants mentioned above, St John's Wort is obtained through herbalists and health food shops in such countries, the exception being Ireland where it can only be obtained on prescription like any other antidepressant. There are at least 12 placebo-controlled studies proving the efficacy of St John's Wort against standard antidepressants; all these studies show that the mixture of compounds present in St John's Wort is effective in mild to moderate, but not severe, depression. Of the main active ingredients of the plant, it would appear that hyperfolin is largely responsible for the antidepressant activity. This compound is an inhibitor of the reuptake of noradrenaline, dopamine and serotonin. In addition, it appears to have some NMDA-glutamate receptor antagonist activity, a property which it shares with many other antidepressants.

A diagram summarizing the sites of action of most classes of antidepressants is illustrated in Figure 7.5.

Physical pain and depression

Major depression is a triad of psychological, somatic and physical symptoms. Over 75% of depressed patients report painful physical symptoms involving the neck, back, head, stomach and the skeleto-muscular system. Not only can chronic pain lead to depression, but also vice versa.

Fibromyalgia, accounting for 2-4% of the general population, is a common cause of chronic pain. It has been estimated that 20-40% of such patients have co-morbid depression with a lifetime prevalence of about 70%. This raises the question whether there is a common mechanism linking pain and depression.

Neuroanatomically both the locus coeruleus and the raphe nuclei project to the spinal cord where they gate sensory pathways from the skeletomuscular areas. As there is evidence that both noradrenaline and 5-HT are dysfunctional in depression, it is perhaps not surprising to find that the pain threshold is often reduced in patients with depression. Conversely, different types of antidepressants have been shown to have an antinociceptive effect in both rodent models of neuropathic pain, and clinically in fibromyalgia, chronic fatigue syndrome, postherpetic neuralgia and diabetic neuropathy. In general, it would appear that the dual action antidepressants (such as the TCAs and SNRIs) are more effective than the SSRIs.

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Figure 7.5. Summary of the sites of action of antidepressants and ECT on the serotonergic neuron.

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Figure 7.5. Summary of the sites of action of antidepressants and ECT on the serotonergic neuron.

Treatment decisions for unipolar depression

• Treatment of choice - second-generation antidepressants such as a SSRI, venlafaxine, mirtazepine, reboxetine, moclobemide.

• Switching - alternative second-generation antidepressant, usually from another group.

• Augmentation of antidepressant response - add lithium, thyroid hormone, an atypical antipsychotic (e.g. risperidone, olanzepine), pindolol, buspirone.

Note: In a survey of 13 studies, switching from an SSRI to either another SSRI or to imipramine, venlafaxine, mirtazepine or buproprion resulted in a response rate of 30-90%.

182 FUNDAMENTALS OF PSYCHOPHARMACOLOGY

Electroconvulsive shock treatment

One of the pioneers in the application of electroconvulsive shock treatment (ECT) was the Italian clinician Cerletti who stated that the "... electricity itself is of little importance . . . the important and fundamental factor is the epileptic-like seizure no matter how it is obtained''. ECT is undoubtedly an effective treatment for a range of psychiatric diseases varying from severe depression and mania to some forms of schizophrenia. Despite the considerable use of ECT over the last 50 years, it still arouses intense emotional and scientific debate. While the opposition to the use of ECT has been more evident in some Continental European countries and the United States than in Britain or Ireland, it was a British study of the use of ECT which, following a survey of over 100 centres, found that many units were badly equipped and had poor facilities and staff training. This report resulted in a considerable improvement in the application of ECT, with the establishment of guidelines governing the management and use of the technique; somewhat similar guidelines were instituted by the American Psychiatric Association.

It is now generally agreed that ECT is singularly effective and useful. There has been controversy over the relative merits in using unilateral or bilateral ECT. In general, it would appear that unilateral ECT is effective in the treatment of most depressed patients, whereas manic patients appear to respond best to bilateral ECT. Following a course of treatment, twice weekly for several weeks, the success rate in treating depression is about 80%. This is more successful than using antidepressants (up to 70% for a single course of treatment). Seizure monitoring is essential to ensure an adequate response. The principal side effect of ECT is a temporary cognitive deficit, specifically memory loss. There is evidence that such impairment is reduced if unilateral ECT is applied to the non-dominant hemisphere. Brief pulse-current ECT machines are now favoured in Britain and the United States to ensure optimal efficacy and minimal side effects. As Cerletti hypothesized in 1938, chemically induced seizures are equally effective as ECT and at one time pentamethylenetetrazole or flurothyl were used to produce seizures. However, the safety and ease of application of ECT means that such methods have been largely replaced.

How does ECT work?

While there are various psychological, neurophysiological and neuroendocrine theories that have been developed to explain the beneficial effects of ECT, most attention has been given to the manner in which ECT causes changes in those neurotransmitters that have been implicated in psychiatric illness. It is known that the rise in the seizure threshold during the course of treatment, and the corresponding alteration in cerebral blood flow, may reflect profound changes in cerebral metabolism that could be of crucial importance regarding the action of ECT. Changes in the hypothalamo-pituitary-adrenal axis have also been reported, but most studies suggest that such changes are secondary to the clinical response. The major emphasis of research has therefore been in the functional changes in brain neurotransmission, but it must be emphasized that most detailed studies have been conducted in rodents and therefore their precise relevance to changes in the human brain are a matter of conjecture.

Experimental studies in rodents have largely centred on the changes in biogenic amine neurotransmitters following chronic ECT treatments. Under these conditions, noradrenaline and 5-HT have been shown to be increased; the number of presynaptic alpha2 receptors and their functional activity has been shown to be decreased, as has the functional activity of the dopamine autoreceptors. Such changes have also been found following the chronic administration of antidepressant drugs. The most consistent changes reported have been those found in postsynaptic receptor function. The functional activity of the postsynaptic beta adrenoceptors is decreased, a change which is also found with antidepressants. The postsynaptic 5-HT2 receptor sensitivity is enhanced by chronic ECT and antidepressant treatment. Thus there appears to be a consistency between the chronic effects of both ECT and antidepressants in enhancing 5-HT responsiveness and diminishing that of noradrenaline. Regarding the dopaminergic system, while there is speculation that changes in the activity of this system may be important in the action of novel antidepressants such as bupropion, the only consistent changes found following chronic application of ECT and antidepressants is a functional decrease in the dopamine autoreceptor activity. This would lead to a reduction in the release of this transmitter.

In contrast to the plethora of animal studies, few clinical studies have shown consistent changes in the biogenic amines. There is evidence that the urinary and CSF concentrations of the noradrenaline metabolites normetanephrine and MHPG are decreased, suggesting that the turnover of noradrenaline is decreased, the opposite to that found in animals. Neuroendocrine challenge tests that have been used as probes to assess central noradrenergic function (e.g. with clonidine) show no consistent changes in patients following chronic ECT. Consistent changes have been reported in serotonergic function, however, with enhanced prolactin release occurring in response to a thyroid-stimulating hormone challenge. This is in agreement with the view that chronic ECT sensitizes postsynaptic 5-HT2 receptors. Furthermore, platelet imipramine binding, which according to the results of some studies is increased in the untreated depressed patient, is attenuated by both antidepressant and ECT treatments, although it must be emphasized that not all investigators can replicate these findings. The transport of [3H]5-HT into the platelets of depressed patients is also normalized following ECT and chronic antidepressant treatments. There is no evidence of any change in the dopaminergic system in depressed patients following ECT.

The central cholinergic system has been implicated in the pathogenesis of affective disorder and in memory function, which is frequently found to be malfunctioning in depressed patients. The memory deficit elicited by chronic ECT in both patients and animals may be related to the decreased density and function of central muscarinic receptors, but it should be emphasized that the changes reported in cholinergic function are small and their relevance to the clinical situation remains to be established.

Brain GABA is closely associated with the induction of seizures. In animals, chronic ECT decreases GABA synthesis in the limbic regions. While consistent changes in GABA-A receptor activity have not been reported, it would appear that GABA-B receptor density increases in the limbic regions following chronic ECT. This is qualitatively similar to the changes that have been reported following antidepressant treatment. The recent interest in the involvement of GABA in the aetiology of depression and in the mode of action of antidepressants is based on the hypothesis that GABA plays a key role not only in the induction of seizures but also in modulating the changes in the serotonergic system that are induced by both antidepressants and ECT.

Due to the ubiquitous distribution of peptides as cotransmitters and neuromodulators in the brain, it is not surprising to find that ECT produces changes in their concentrations and in their possible functional activity. Increased metenkephalin concentrations have been reported following chronic ECT. Such changes may be due to increased opioid receptor binding sites. Opioid-mediated behavioural changes such as catalepsy and reduced pain responses are increased following ECT in animals. Whether such changes are relevant to the effects of ECT and antidepressants in depressed patients is still unknown.

Other possibilities that have been suggested as a cause of the antidepressant action of ECT include an enhanced adenosine1 receptor density in the cortex; agonists at these receptor sites are known to have anticonvulsant properties, while antagonists such as caffeine can cause convulsions, at least in high doses. Thyroid-stimulating hormone activity has also been shown to be enhanced. This peptide may exert antidepressant effects in its own right, but may also act by modulating both serotonergic and dopaminergic activity.

In SUMMARY, it would appear that ECT produces a number of changes in central neurotransmission that are common to antidepressants. These include a decrease in the functional activity of beta adrenoceptors and an enhanced activity of 5-HT2 and possibly GABA-B receptors. The functional defect in central muscarinic receptors may be associated with the memory deficits caused by ECT treatment. It must be emphasized that the changes reported have largely been derived from animal experiments and their precise relevance to the mode of action of ECT in man is still a matter of conjecture.

Adverse effects of drug treatment for depression

TCAs

Significant side effects have been estimated to occur in about 5% of patients on TCAs, most of these effects being attributed to their antimuscarinic properties, for example, blurred vision, dry mouth, tachycardia and disturbed gastrointestinal and urinary tract function. Orthostatic hypotension due to the block of alpha1 adrenoceptors and sedation resulting from antihistaminic activity frequently occur at therapeutic doses, particularly in the elderly. Excessive sweating is also a fairly common phenomenon, but its precise mechanism is uncertain. In the elderly patient, the precipitation of prostatic hypertrophy and glaucoma by the TCAs is also a frequent cause of concern.

Adverse effects of the TCAs on the brain include confusion, impaired memory and cognition and occasionally delirium; some of these effects have been reported to occur in up to 30% of patients over the age of 50. These effects may occasionally be confused with a recurrence of the symptoms of depression and are probably due to the central antimuscarinic activity of these drugs. Tremor also occurs frequently, particularly in the elderly, and may be controlled by the concurrent administration of propranolol. Neuroleptics are normally not recommended to be used in combination with TCAs as they are liable to accentuate the side effects of the latter drugs. The risk of seizures, and the switch from depression to mania in bipolar patients, has also been reported following TCA administration.

Weight gain is a frequent side effect and is of considerable concern, particularly in the female patient, an effect probably associated with increased appetite. Other less common side effects include jaundice (particularly with imipramine), agranulocytosis and skin rashes.

Acute poisoning

This occurs all too frequently with the TCAs and can be life threatening. Death has been reported with doses of 2000 mg of imipramine, or the equivalent quantity of other TCAs, which approximates to 10 daily doses or less! Severe intoxication has been reported at doses of 1000 mg. Because of

Table 7.11. Relative toxicity of antidepressants in overdose (UK data for period

1985-1990)

Table 7.11. Relative toxicity of antidepressants in overdose (UK data for period

1985-1990)

Drug

Deaths per million prescriptions

Tricyclics

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Natural Pain Management

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