Why is there a delay in the onset of the antidepressant response?
In an attempt to explain the reason for the delay in the onset of the therapeutic effect of antidepressants, which is clearly unrelated to the acute actions of these drugs on monoamine reuptake transporters or intracellular metabolizing enzymes, emphasis has moved away from the presynaptic mechanism governing the release of the monoamine transmitters to the adaptive changes that occur in pre- and postsynaptic receptors that govern the physiological expression of neurotransmitter function.
Antidepressant therapy is usually associated with a gradual onset of action over 2 to 3 weeks before the optimal beneficial effect is obtained. Much of the improvement seen early in the treatment with antidepressants is probably associated with a reduction in anxiety that often occurs in the depressed patient and improvement in sleep caused by the sedative action of many of these drugs. The delay in the onset of the therapeutic response cannot be easily explained by the pharmacokinetic profile of the drugs as peak plasma (and presumably brain) concentrations are usually reached in 7 to 10 days. Furthermore, the 2-3 weeks delay is also seen in many, though not all, patients given electroconvulsive therapy (ECT). Table 7.4 summarizes some of the changes in neurotransmitter receptors that occur in the cortex of rat brain following ECT or the chronic administration of antidepressants. From the results of such studies, it is apparent that adaptational changes occur in adrenoceptors, serotonin, dopamine and
Table 7.4. Changes in cholinergic and aminergic receptors in depression and following antidepressant treatment
1. Evidence that central muscarinic receptors are supersensitive in depressed patients and that chronic antidepressant treatments normalize the super-sensitivity of these receptors. This effect does not depend on any intrinsic anticholinergic activity of the antidepressant (i.e. it is an indirect, adaptive effect).
2. Following chronic administration to rats, there is evidence that most anti-depressants cause adaptive changes in 5-HTia, 5-HT2A alpha-1, alpha-2 and beta adrenoceptors, GABA-B receptors and possibly the NMDA-glutamate receptors.
GABA-B receptors. There is evidence that GABA-B receptors play a role in enhancing noradrenaline release in the cortex and in this respect differ fundamentally from the inhibitory GABA-A receptors which facilitate central GABAergic transmission. A decrease in the activity of GABA-B receptors may therefore contribute to the reduced central noradrenergic tone reported to occur in depression.
In addition to these changes, recent evidence has shown that a decrease in cortical muscarinic receptors occurs in the bulbectomized rat model of depression that, like most of the changes in biogenic amine receptors, returns to control values following treatment with either typical (e.g. tricyclic antidepressants) or atypical (e.g. mianserin) antidepressants. Such findings are of particular interest as the anticholinergic activity of the tricyclic antidepressants is usually associated with their unacceptable peripheral side effects and most second generation antidepressants have gained in therapeutic popularity because they lack such side effects. Nevertheless, support for the cholinergic hypothesis of depression is provided by the finding that the short-acting reversible cholinesterase inhibitor pyridostigmine, when administered to drug-free depressed patients, causes an enhanced activation of the anterior pituitary gland as shown by the release of growth hormone secretion. This suggests that the muscarinic receptors are supersensitive in the depressed patient. However, the mechanism whereby the receptors are normalized by chronic (but not acute) antidepressant treatment vary and in most cases are unlikely to be due to a direct anticholinergic action. It has been postulated that depression arises as the result of an imbalance between the central noradrenergic and cholinergic systems; in depression the activity of the former system is decreased and, conversely, in mania it is increased. As most antidepres-sants, irrespective of the presumed specificity of their action on the noradrenergic and serotonergic systems, have been shown to enhance noradrenergic function, it is hypothesized that the functional reduction in cholinergic activity arises as a consequence of the increase in central noradrenergic activity.
In SUMMARY, irrespective of the specificity of the antidepressants following their acute administration, it can be speculated that a common feature of all these drugs is to correct the abnormality in neurotransmitter receptor function. Such an effect of chronic antidepressant treatment may parallel the time of onset of the therapeutic response and contribute to the receptor sensitivity hypothesis of depression and the common mode of action of antidepressants.
The link between the serotonergic and noradrenergic systems
Considerable attention has recently been focused on the interaction between serotonergic and beta-adrenergic receptors, which may be of particular relevance to our understanding of the therapeutic effect of antidepressants. Thus the chronic administration of antidepressants enhances the inhibitory response of forebrain neurons to micro-iontophoretically applied 5-HT. This enhanced response is blocked by lesions of the noradrenergic projections to the cortex. This dual effect could help to explain enhanced serotonergic function that arises after chronic administration of anti-depressants or ECT. Conversely, impairment of serotonergic function by means of a selective neurotoxin (e.g. 5,7-dihydroxytryptamine) or 5-HT synthesis inhibitor (e.g. parachlorophenylalanine) largely prevents the decrease in functional activity of cortical beta-adrenoceptors that usually arises following chronic antidepressant treatment. 5-HT1B receptors are located on serotonergic nerve terminals that act as autoreceptors, and, on stimulation by serotonin, decrease the further release of this amine. It has been hypothesized that the chronic administration of selective serotonin reuptake inhibitor antidepressants (such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine) slowly desensitize the inhibitory 5-HT1B receptors and thereby enhance serotonin release.
In addition to the importance of the 5-HT1B autoreceptors in the regulation of serotonergic function, there is experimental and clinical evidence that the 5-HT1A receptors play a fundamental role in both anxiety and depression. In brief, the 5-HT1A somatodendritic receptors inhibit the release of serotonin and it is postulated that the enhanced release of the transmitter following the chronic administration of the selective serotonin reuptake inhibitors is a consequence of the adaptive down-regulation of the inhibitory 5-HT1A receptors. The validity of this hypothesis is supported by the pharmacological effect of 5-HT1A antagonists. Thus the beta-adreno-ceptors antagonist and 5-HT1A antagonist pindolol, in combination with fluoxetine or paroxetine, enhance the therapeutic efficacy of the SSRI and, in some studies, reduce the time of onset of the peak therapeutic effect. However, several investigators have not been able to replicate such findings.
Both clinical and experimental studies have provided evidence that 5-HT can also regulate dopamine turnover. Thus several investigators have shown that a positive correlation exists in depressed patients between the homovanillic acid (HVA), a major metabolite of dopamine, and 5-HIAA concentrations in the CSF. In experimental studies, stimulation of the 5-HT cell bodies in the median raphe causes reduced firing of the substantia nigra where dopamine is the main neurotransmitter. There is thus convincing evidence that 5-HT plays an important role in modulating dopaminergic
Table 7.5. Mechanism of action of antidepressants: changes in serotonergic function
1. There is experimental evidence that the chronic administration of antidepressants or ECT enhances the inhibitory effect of micro-iontophoretically applied 5-HT. This effect is blocked by lesions of the noradrenergic projections to the frontal cortex.
2. SSRIs after chronic administration down-regulate the inhibitory 5-HTja receptors on the serotonergic cell body, thereby leading to an enhanced release of the transmitter from the nerve terminal.
3. 5-HT can also decrease dopamine release from the substantia nigra (an important dopaminergic nucleus). This may account for the observation that some SSRIs may cause dystonias and precipitate the symptoms of parkinsonism if given to such patients who are responding to L-dopa. Sertraline appears to differ from other SSRIs in this respect and may slightly enhance dopaminergic function by reducing the reuptake of this transmitter.
function in many regions of the brain, including the mesolimbic system. Such findings imply that the effects of some antidepressants that show an apparent selectivity for the serotonergic system could be equally ascribed to a change in dopaminergic function in mesolimbic and mesocortical regions of the brain. It has been postulated that the hedonic effect of antidepressants may be ascribed to the enhanced dopaminergic function in the mesocortex (Table 7.5).
The role of the glutamatergic system in the action of antidepressants
Whereas much emphasis has been placed on the monoamine neurotrans-mitters with respect to the mechanism of action of antidepressants, little attention has been paid to the changes in the glutamate system, the primary excitatory neurotransmitter pathway in the brain. Experimental evidence shows that tricyclic antidepressants inhibit the binding of dizolcipine to the ion channel of the main glutamate receptor, the N-methyl-D-aspartate receptor in the brain. The initial studies have more recently been extended to show that both typical and atypical antidepressants have a qualitatively similar effect by reducing the binding of dizolcipine to the NMDA receptors. Whether this is due to direct action of the antidepressants on the ion channel receptor sites, or an indirect effect possibly involving the modulation of the glycine receptor site, is uncertain, but there is evidence that glycine and drugs modulating the glycine site have antidepressant-like activity in animal models of depression. These results suggest that antidepressants act as functional NMDA receptor antagonists.
Intracellular changes that occur following chronic antidepressant treatment
The recent advances in molecular neurobiology have demonstrated how information is passed from the neurotransmitter receptors on the outer side of the neuronal membrane to the secondary messenger system on the inside. The coupling of this receptor to the secondary messenger is brought about by a member of the G protein family. Beta-adrenoceptors are linked to adenylate cyclase, and, depending on the subtype of receptors, 5-HT is linked to either adenylate cyclase (5-HT1A, 5-HT1B) or phospholipase (5-HT2A, 5-HT2c). Activation of phospholipase results in an intracellular increase in the secondary messengers diacylglycerol and inositol triphos-phate (IP3), the IP3 then mobilizing intraneuronal calcium.
The net result of the activation of the secondary messenger systems is to increase the activity of the various protein kinases that phosphorylate membrane-bound proteins to produce a physiological response. Some researchers have investigated the effect of chronic antidepressant treatment on the phosphorylation of proteins associated with the cytoskeletal structure of the nerve cell. Their studies suggest that antidepressants could affect the function of the cytoskeleton by changing the component of the associated protein phosphorylation system. In support of their hypothesis, these researchers showed that both typical (e.g. desipramine) and atypical (e.g. (+) oxaprotiline, a specific noradrenaline reuptake inhibitor, and fluoxetine, a selective 5-HT uptake inhibitor) antidepressants increased the synthesis of a microtubule fraction possibly by affecting the regulatory subunit of protein kinase type II. These changes in cytoskeletal protein synthesis occurred only after chronic antidepressant treatments and suggest that antidepressants, besides their well-established effects on pre- and postsynaptic receptors and amine uptake systems, might change neuronal signal transduction processes distal to the receptor (Table 7.6).
Glucocorticoid receptors: adaptive changes following antidepressant treatment
Interest in the possible association of glucocorticoid receptors with central neurotransmitter function arose from the observation that such receptors have been identified in the nuclei of catecholamine and 5-HT-containing cell bodies in the brain. Experimental studies have shown that glucocorticoid receptors activate as DNA binding proteins which can modify the transcription of genes. The link to antidepressant treatments is indicated by the chronic administration of imipramine which increases glucocorticoid receptor immunoreactivity in rat brain, the changes being particularly pronounced in the noradrenergic and serotonergic cell body regions.
Table 7.6. Possible role of excitatory amino acids and intracellular second messengers in the action of antidepressants
1. In experimental studies, chronic antidepressant treatments have been shown to reduce the behavioural effects of the NMDA-glutamate receptor antagonist dizolcipine. This suggests that antidepressants may act as functional NMDA receptor antagonists and thereby reduce excitatory glutamate transmission which is mediated by NMDA receptors.
2. Intracellular protein phosphorylation is enhanced by chronic antidepressant treatment. This leads to the increased synthesis of microtubules that form an important feature of the cellular cytoskeleton. Thus antidepressants might change signal transduction with the neurone.
3. Enhanced synthesis and transport of neurotransmitter synthesizing enzymes (e.g. tyrosine and tryptophan hydroxylase).
Preliminary clinical studies have shown that lymphocyte glucocorticoid receptors are subsensitive in depressed patients. The failure of the negative feedback mechanism that regulates the secretion of adrenal glucocorticoids further suggests that the central glucocorticoid receptors are subsensitive. This leads to the hypersecretion of cortisol, a characteristic feature of many patients with major depression. Such findings lend support to the hypothesis that the changes in central neurotransmission occurring in depression are a reflection of the effects of chronic glucocorticoids on the transcription of proteins that play a crucial role in neuronal structure and function.
If the pituitary-adrenal axis plays such an important role in central neurotransmission, it may be speculated that glucocorticoid synthesis inhibitors (e.g. metyrapone) could reduce the abnormality in neurotrans-mitter function by decreasing the cortisol concentration.
Recent in vitro hybridization studies in the rat have demonstrated that typical antidepressants increase the density of glucocorticoid receptors. Such an effect could increase the negative feedback mechanism and thereby reduce the synthesis and release of cortisol. In support of this hypothesis, there is preliminary clinical evidence that metyrapone (and the steroid synthesis inhibitor ketoconazole) may have antidepressant effects. Recently several lipophilic antagonists of corticotrophin releasing factor (CRF) type 1 receptor, which appears to be hyperactive in the brain of depressed patients, have been shown to be active in animal models of depression. Clearly this is a potentially important area for antidepressant development.
Glucocorticoid receptors are present in a high density in the amygdala and neuroimaging studies have shown that the amygdala is the only structure in which the regional blood flow and glucose metabolism consistently correlate positively with the severity of depression. This
Table 7.7. Role of glucocorticoids in modulating brain amines in depression
1. Glucocorticoid receptors occur on catecholamine and 5-HT cell bodies in the brain.
2. There is evidence that the glucocorticoid receptors are hyposensitive in the depressed patients.
3. Chronic antidepressant treatment sensitizes these receptors, thereby normalizing the noradrenergic and serotonergic function that is reduced by the hyper-cortisolaemia which occurs in major depression.
hypermetabolism appears to reflect an underlying pathological process as it also occurs in asymptomatic patients and in the close relatives of the patients (Table 7.7).
The effects of antidepressants on endocrine-immune functions
Stress is frequently a trigger factor for depression in vulnerable patients. There is clinical evidence to show that CRF is elevated in the cerebrospinal fluid of untreated depressed patients, which presumably leads to the hypercortisolaemia that usually accompanies the condition. One of the consequences of elevated plasma glucocorticoids is a suppression of some aspects of cellular immunity. It is now established that many cellular (for example, natural killer cell activity, T-cell replication) and non-cellular (for example, raised acute phase proteins) aspects are abnormal in the untreated depressed patient. Such observations could help to explain the susceptibility of depressed patients to physical ill health.
A link between CRF, the cytokines which orchestrate many aspects of cellular immunity, and the prostaglandins of the E series has been the subject of considerable research in recent years. There is clinical evidence to show that prostaglandin E2 (PGE2) concentrations are raised in the plasma of untreated depressed patients and are normalized following effective treatment with tricyclic antidepressants. Raised PGE2 concentrations in the brain and periphery reflect increased proinflammatory cytokines (particularly tumour necrosis factor, interleukins 1 and 6) which occur as a consequence of increased macrophage activity in the blood and brain. In the brain the microglia functions as macrophages and produces such cytokines locally. Thus the increased synthesis of PGE2 may contribute to the reduction in amine release in the brain that appears to underlie the pathology of depression. It has recently been postulated that several types of antidepressants (e.g. tricyclics, monoamine oxidase inhibitors) normalize central neurotransmission by reducing brain concentrations of both the cytokines and PGE2 by inhibiting central and peripheral macrophage activity together with cyclooxygenase type 2 activity in the brain. Cyclooxygenase is the key enzyme in the synthesis of the prostaglandins. It is not without interest that the usefulness of tricyclic antidepressants in
Table 7.8. The possible role of prostaglandins and cytokines in depression
1. There is evidence that both cellular and non-cellular immunity are abnormal in the depressed patient.
2. The proinflammatory cytokines (interleukins 1 and 6 and tumour necrosis factor alpha) from macrophages are raised in depression. This leads to increased PGE2 synthesis and release which may lead to a reduction in central monoamine release.
3. Chronic antidepressant treatments reduce both the proinflammatory cytokines and PGE2.
severe rheumatoid arthritis can now be explained by the inhibitory action of such drugs on cyclooxygenase activity in both the periphery and brain. Such changes, together with those in glucocorticoid receptor function, may therefore incrementally bring about the normalization of defective central neurotransmission as a consequence of antidepressant treatment. Whether the inhibition of cyclooxygenase is a common feature of all classes of antidepressants is presently unknown (Table 7.8).
Another possible mechanism whereby antidepressants may change the physical relationship between neurons in the brain is by inhibiting neurite outgrowth from nerve cells. In support of this view, it has been shown that the tricyclic antidepressant amitriptyline, at therapeutically relevant concentrations, inhibited neurite outgrowth from chick embryonic cerebral explants in vivo. While the relevance of such findings to the therapeutic effects of amitriptyline in man is unclear, they do suggest that a common mode of action of all antidepressants could be to modify the actual structure of nerve cells and possibly eliminate inappropriate synaptic contacts that are responsible for behavioural and psychological changes associated with depression.
There are several mechanisms whereby antidepressants can modify intracellular events that occur proximal to the postsynaptic receptor sites. Most attention has been paid to the actions of antidepressants on those pathways that are controlled by receptor-coupled second messengers (such as cyclic AMP, inositol triphosphate, nitric oxide and calcium binding). However, it is also possible that chronic antidepressant treatment may affect those pathways that involve receptor interactions with protein tyrosine kinases, by increasing specific growth factor synthesis or by regulating the activity of proinflammatory cytokines. These pathways are particularly important because they control many aspects of neuronal function that ultimately underlie the ability of the brain to adapt and respond to pharmacological and environmental stimuli. One mechanism whereby antidepressants could increase the synthesis of trophic factors is
Table 7.9. Changes in neuronal structure in depression
1. There is evidence that inadequately treated, or untreated, major depression is associated with a decrease in the hippocampal volume. This could be a consequence of the increase in proinflammatory cytokines and hypercortisol-aemia.
2. Experimental evidence suggests that chronic antidepressant treatments increase the formation of transcription factors within the brain which increases neuronal plasticity and leads to recovery.
by the activation of cyclic AMP-dependent protein kinase which indirectly increases the formation of the transcription factors. There is experimental evidence to show that the infusion of one of these transcription factors (brain derived neutrophic factor) into the midbrain of rats results in antidepressant-like activity, an action associated with an increase in the synthesis of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin (Table 7.9).
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