Historical development of antidepressants
The use of cocaine, extracted in a crude form from the leaves of the Andean coca plant, has been used for centuries in South America to alleviate fatigue and elevate the mood. It was only relatively recently, however, that the same pharmacological effect was discovered when the amphetamines were introduced into Western medicine as anorexiants with stimulant properties. Opiates, generally as a galenical mixture, were also widely used for centuries for their mood-elevating effects throughout the world. It is not without interest that while such drugs would never now be used as antidepressants, there is evidence that most antidepressants do modulate the pain threshold, possibly via the enkephalins and endorphins. This may help to explain the use of antidepressants in the treatment of atypical pain syndromes and as an adjunct to the treatment of terminal cancer pain. Finally, alcohol in its various forms has been used to alleviate anguish and sorrow since antiquity. Whilst the opiates, alcohol and the stimulants offer some temporary relief to the patient, their long-term use inevitably leads to dependence and even to an exacerbation of the symptoms they were designed to cure. The development of specific drugs for the treatment of depression only occurred in the early 1950s with the accidental discovery of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). This period marked the beginning of the era of pharmacopsychiatry. Although the iminodibenzyl structure, which forms the chemical basis of the TCA series, was first synthesized in 1889, its biological activity was only evaluated in the early 1950s following the accidental discovery that the tricyclic compound chlorpromazine had antipsychotic properties. Imipramine is also chemically similar in structure to chlorpromazine, but was found to lack its antipsychotic effects. It was largely due to the persistence of the Swiss psychiatrist Kuhn that imipramine was not discarded and was shown to have specific antidepressant effects. It is not without interest that the first report of the antidepressant effects of imipramine was presented to an audience of 12 as part of the proceedings of the Second World Congress of Psychiatry in Zurich in 1957! The introduction of the first MAOI in the early 1950s was equally inauspicious. Iproniazid had been developed as an effective hydrazide antitubercular drug, but was subsequently found to exhibit mood-elevating effects. This was shown to be due to its ability to inhibit MAO activity and was unconnected with its antitubercular action. Thus by the late 1950s, psychiatrists had at their disposal two effective treatments for depression, a TCA and an MAOI. But it was only in attempting to discover how these drugs may work, together with the evidence that the recently introduced antipsychotic drug resperine caused depression in a small number of patients, that the hypothesis was developed that depression was due to a relative deficit of biogenic amine neurotransmitters in the synaptic cleft and that antidepressants reversed this deficit by preventing their inactivation.
While this hypothesis has been drastically revised in the light of research into the biochemical nature of depression, at that time it had the advantage of unifying a number of disparate clinical and experimental observations and in laying the basis for subsequent drug development. Aspects of the biochemical basis of depression Research into the chemical pathology of depression has mainly concentrated on four major areas:
1. Changes in biogenic amine neurotransmitters in post-mortem brains from suicide victims.
2. Changes in cerebrospinal fluid (CSF) concentrations of amine metabolites from patients with depression.
3. Endocrine disturbances which appear to be coincidentally related to the onset of the illness.
4. Changes in neurotransmitter receptor function and density on platelets and lymphocytes from patients before and following effective treatment.
Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methylparatyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brains of suicide victims. The problem with such post-mortem studies is that (a) the precise diagnosis may be uncertain, (b) there is usually a considerable postmortem delay before the brain is removed at autopsy and (c) suicide is often committed by taking an overdose of alcohol together with drugs which grossly affect central monoamine neurotransmitter function. Unless these variables are carefully controlled, the value of the results obtained from such analyses is uncertain. Nevertheless, there is evidence that the neurotransmitter receptors in post-mortem brain are less labile than the neurotransmitters that act upon them. The finding that the density of beta adrenoceptors is increased in cortical regions of the brains from suicide victims who had suffered from depression is evidence of disturbed noradrenergic function which is associated with some of the symptoms of the illness. Such observations are further supported by the increase in the density of beta adrenoceptors on the lymphocytes of untreated depressed patients. As t he density of these receptors is normalized by effective antidepressant treatment, it has been postulated that changes in the beta receptor density may be a state marker of the condition. Other studies have shown that the elevation of growth hormone in the plasma following the administration of the alpha-2 adrenoceptor agonist clonidine is diminished in depressed patients, which suggests that central postsynaptic alpha-2 adrenoceptors are also subfunctional in such patients. This is perhaps the most consistent finding to have emerged in studies of the hypothalamic–pituitary axis in depression. As the clonidine response does not return to normal after effective antidepressant treatment, this is possibly a trait marker of depression. It should be emphasized that the reduced growth hormone response to clonidine cannot be accounted for by drug treatment, age or gender of the patient, which supports the view that the noradrenergic system is dysregulated in depression. Lastly, determination of the urine or plasma concentrations of MHPG (an indicator of central noradrenergic activity) suggests that central noradrenergic function is suboptimal in depression. Taken together, these results suggest that central noradrenergic function is decreased in depression, an event leading to the increase in the density of the postsynaptic beta adrenoceptors that show adaptive changes in response to the diminished synaptic concentration of the transmitter. It should be emphasized however that none of the studies of noradrenergic function in post-mortem material or tissues from depressed patients are entirely satisfactory. Many of the findings cannot be replicated, the number of patients studied is relatively small and the tritiated ligands used to determine the receptor density for example vary in their selectivity.
There is also evidence that the density of muscarinic receptors is increased in limbic regions of depressed patients who have committed suicide. If it is assumed that such a change reflects an increased activity of the cholinergic system, it could help to explain the reduced noradrenergic function as there is both clinical and experimental evidence to suggest that increased central cholinergic activity can precipitate depression and reduce noradrenergic activity. The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psychophysiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2A receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. Thus platelets are, like neurons, of ectodermal origin and contain enzymes such as enolase that are otherwise restricted to neurons. In addition, platelets contain storage vesicles for 5-HT from which the amine is released by a calcium-dependent mechanism. An energy-dependent transport site for 5-HT also occurs on the platelet membrane, the structure of which is identical to that found on neurons in the brain. Furthermore, the platelet membrane contains 5-HT2A and alpha-2 adrenergic receptors that are functionally involved in platelet aggregation; there is evidence that the densities of these receptors are increased in depressed patients and largely normalized following effective treatment. Thus a number of important biochemical parameters may be determined from a platelet-rich plasma sample. It has been found, for example, that the transport of 3H-5-HT into the platelet is significantly reduced in the untreated depressed patient but largely returns to normal following effective treatment. This change occurs irrespective of the nature of the antidepressant used to treat the patient and may therefore be considered as a state marker of the illness. The function of the 5-HT2A receptor also appears to be subnormal in the untreated patient as shown by diminished aggregatory response to the addition of 5-HT in vitro, but normalizes when the patient recovers. As the number of 5-HT2A receptors on the platelet membrane of depressed patients is increased (as shown by the increased binding of a specific ligand such as 3H-ketanserin) this finding suggests that the G protein transducer mechanism, which links the receptor to the second messenger phosphatidyl inositol system within the platelet, is possibly defective in depression. There is also evidence that the modulatory site on the 5-HT transporter, the imipramine binding site, is decreased in depression, but unlike the changes in 5-HT uptake, remains unchanged by effective treatment. This suggests that the number of imipramine binding sites on the platelet membrane is a trait marker of the condition. However, the precise relevance of this finding is uncertain as the binding of the more specific ligand, 3H-paroxetine, is unchanged in depression. These studies of platelet function before, during and following treatment can give important information of the biochemical processes which may be causally related to depression. However, it is still uncertain how the changes in platelet function precisely reflect those occurring in the brain. Platelets are unconnected with the nervous system and therefore the changes observed could be a reflection of the hormonal changes (for example, glucocorticoids) that occur in depression. There is also evidence that some of the alterations in platelet function are a consequence of low molecular weight plasma factors that occur in the depressed patient and which are absent following effective antidepressant treatment.
Changes in brain and tissue amine neurotransmitters in depressed patients which may be indicative of the mechanism of action of antidepressants
. Evidence from the brains of depressed patients who committed suicide
. Increased density of beta adrenoceptors in cortical regions
. Increased density of 5-HT2A receptors in limbic regions
. Decreased concentration of 5-HIAA in several brain regions
. Increased muscarinic receptor density in limbic regions
Other clinical studies implicating an abnormal biogenic amine function in depression
. Decreased 5-HIAA concentration in CSF
. Decreased HVA (main dopamine metabolite) in CSF
. Decreased urinary excretion of the main central noradrenaline metabolite MHPG (?)
. Rapid relapse following administration of a tryptophan-free amino acid drink to depressed patients being treated with an SSRI
. Rapid relapse following administration of the tyrosine hydroxylase inhibitor alpha-methyl-tyrosine to depressed patients who respond to a noradrenaline reuptake inhibitor such as desipramine
While there has been considerable attention devoted to changes in noradrenergic and serotonergic function in depression, less attention has been paid to the possible involvement of dopamine in this disorder. This is surprising as anhedonia is a characteristic feature of major depression and a defect in dopaminergic function is thought to be causally involved in this symptom. Several studies have shown that the concentration of the main dopamine metabolite, homovanillic acid (HVA), is decreased in the CSF of depressed patients, particularly those with psychomotor retardation. These depressed patients who attempted suicide were also found to have a decreased urinary excretion of HVA and the second major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). It is of course possible that the dopamine deficit is more a reflection of the degree of retardation rather than the psychological state as similar changes in CSF HVA concentrations have been reported to occur in patients with Parkinson’s disease. This imp lies that the changes in the basal ganglia probably overshadow any changes in the mesolimbic dopaminergic system as the contribution of this area is relatively minor. With regard to the specific action of antidepressants on the dopaminergic system, there is evidence that buproprion (not marketed in most countries in Western Europe as an antidepressant but available in North America), amineptine and nomifensin (withdrawn because of the rare occurrence of haemolysis) owed their antidepressant efficacy to their ability to increase central dopaminergic function. There are also open label studies to suggest that the novel dopamine receptor agonist roxindole and the selective dopamine uptake inhibitor pramipexole may have antidepressant action. Thus when the results of the studies on platelets, lymphocytes, changes in cerebrospinal fluid metabolites of brain monoamines and the post-mortem studies are taken into account it may be concluded that a major abnormality in both noradrenergic and serotonergic function occu rs in depression, and that such changes could be causally related to the disease process.
Evidence from depressed patients
. Increased density of 5-HT2A receptors on the platelet membrane
. Decreased uptake of 3H-5-HT into platelet
. Increased beta adrenoceptor density on lymphocyte membrane
. Increased density of alpha-2 adrenoceptors on platelet membranes (*)
. Blunted growth hormone response to a clonidine challenge
. Blunted prolactin response to a fenfluramine challenge
Both clinical and experimental studies have shown that a number of transmitter receptors and amine transport processes show circadian changes. It is well established that depression is associated with a disruption of the circadian rhythm as shown by changes in a number of behavioural, autonomic and neuroendocrine aspects. One of the main consequences of effective treatment is a return of the circadian rhythm to normality. For example, it has been shown that the 5-HT uptake into the platelets of depressed patients is largely unchanged between 0600 and 1200 hours, whereas the 5-HT transport in control subjects shows a significant decrease over this period. The normal rhythm in 5-HT transport is only reestablished when the depressed patient responds to treatment. Thus it may be hypothesized that the mode of action of antidepressants is to normalize disrupted circadian rhythms. Only when the circadian rhythm has returned to normal can full clinical recovery be established. Chronobiological studies have shown tha circadian rhythms occur in the responsivity of animals to light, dark and psychotropic drugs. This implies that the timing of drug administration so that the drug reaches the target organ at its optimum sensitivity could help to improve its therapeutic efficiency. The results of experimental studies suggest that most antidepressants delay the circadian phase and lengthen the circadian period. These changes could be due to the drugs acting on the circadian pacemaker in the superchiasmatic nucleus. However, other brain regions could also be responsible together with antidepressantinduced changes in the retina which would lead to a modification of the processing of light stimuli; the lateral geniculate nucleus may also have a role to play. Seasonal affective disorder (SAD) generally consists of recurrent depressive episodes in autumn and winter that alternate with euthmia or hypomania in spring and summer. The seasonal rhythms of mood, sleep and weight change seen in SAD patients resemble hibernation seen in animals. This led to the hypothesis that extension of the photoperiod in winter could counteract the depressive symptoms. Exposure to bright light had indeed been shown to be efficacious. Clinical studies show that carbohydrate craving, a common feature of SAD, is possibly linked to a decreased serotonin turnover. Such a hypothesis is supported by the fact that the serotonin releasing agent D-fenfluramine is effective in treating SAD. Chronobiology is clearly an important area of research for the psychopharmacologist which needs more attention.
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). It is apparent that adaptational changes occur in adrenoceptors, serotonin, dopamine and 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.
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 supersensitivity 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 antidepressants cause adaptive changes in 5-HT1A, 5-HT2A alpha-1, alpha-2 and beta adrenoceptors, GABA-B receptors and possibly the NMDA-glutamate receptors.
Changes in cholinergic function
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 antidepressants, 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.
The use of cocaine, extracted in a crude form from the leaves of the Andean coca plant, has been used for centuries in South America to alleviate fatigue and elevate the mood. It was only relatively recently, however, that the same pharmacological effect was discovered when the amphetamines were introduced into Western medicine as anorexiants with stimulant properties. Opiates, generally as a galenical mixture, were also widely used for centuries for their mood-elevating effects throughout the world. It is not without interest that while such drugs would never now be used as antidepressants, there is evidence that most antidepressants do modulate the pain threshold, possibly via the enkephalins and endorphins. This may help to explain the use of antidepressants in the treatment of atypical pain syndromes and as an adjunct to the treatment of terminal cancer pain. Finally, alcohol in its various forms has been used to alleviate anguish and sorrow since antiquity. Whilst the opiates, alcohol and the stimulants offer some temporary relief to the patient, their long-term use inevitably leads to dependence and even to an exacerbation of the symptoms they were designed to cure. The development of specific drugs for the treatment of depression only occurred in the early 1950s with the accidental discovery of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). This period marked the beginning of the era of pharmacopsychiatry. Although the iminodibenzyl structure, which forms the chemical basis of the TCA series, was first synthesized in 1889, its biological activity was only evaluated in the early 1950s following the accidental discovery that the tricyclic compound chlorpromazine had antipsychotic properties. Imipramine is also chemically similar in structure to chlorpromazine, but was found to lack its antipsychotic effects. It was largely due to the persistence of the Swiss psychiatrist Kuhn that imipramine was not discarded and was shown to have specific antidepressant effects. It is not without interest that the first report of the antidepressant effects of imipramine was presented to an audience of 12 as part of the proceedings of the Second World Congress of Psychiatry in Zurich in 1957! The introduction of the first MAOI in the early 1950s was equally inauspicious. Iproniazid had been developed as an effective hydrazide antitubercular drug, but was subsequently found to exhibit mood-elevating effects. This was shown to be due to its ability to inhibit MAO activity and was unconnected with its antitubercular action. Thus by the late 1950s, psychiatrists had at their disposal two effective treatments for depression, a TCA and an MAOI. But it was only in attempting to discover how these drugs may work, together with the evidence that the recently introduced antipsychotic drug resperine caused depression in a small number of patients, that the hypothesis was developed that depression was due to a relative deficit of biogenic amine neurotransmitters in the synaptic cleft and that antidepressants reversed this deficit by preventing their inactivation.
While this hypothesis has been drastically revised in the light of research into the biochemical nature of depression, at that time it had the advantage of unifying a number of disparate clinical and experimental observations and in laying the basis for subsequent drug development. Aspects of the biochemical basis of depression Research into the chemical pathology of depression has mainly concentrated on four major areas:
1. Changes in biogenic amine neurotransmitters in post-mortem brains from suicide victims.
2. Changes in cerebrospinal fluid (CSF) concentrations of amine metabolites from patients with depression.
3. Endocrine disturbances which appear to be coincidentally related to the onset of the illness.
4. Changes in neurotransmitter receptor function and density on platelets and lymphocytes from patients before and following effective treatment.
Approximately 30 years ago, Schildkraut postulated that noradrenaline may play a pivotal role in the aetiology of depression. Evidence in favour of this hypothesis was provided by the observation that the antihypertensive drug reserpine, which depletes both the central and peripheral vesicular stores of catecholamines such as noradrenaline, is likely to precipitate depression in patients in remission. The experimental drug alpha-methylparatyrosine that blocks the synthesis of noradrenaline by inhibiting the rate-limiting enzyme tyrosine hydroxylase was also shown to precipitate depression in patients during remission. While such findings are only indirect indicators that noradrenaline plays an important role in human behaviour, and may be defective in depression, more direct evidence is needed to substantiate the hypothesis. The most obvious approach would be to determine the concentration of noradrenaline and/or its major central metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brains of suicide victims. The problem with such post-mortem studies is that (a) the precise diagnosis may be uncertain, (b) there is usually a considerable postmortem delay before the brain is removed at autopsy and (c) suicide is often committed by taking an overdose of alcohol together with drugs which grossly affect central monoamine neurotransmitter function. Unless these variables are carefully controlled, the value of the results obtained from such analyses is uncertain. Nevertheless, there is evidence that the neurotransmitter receptors in post-mortem brain are less labile than the neurotransmitters that act upon them. The finding that the density of beta adrenoceptors is increased in cortical regions of the brains from suicide victims who had suffered from depression is evidence of disturbed noradrenergic function which is associated with some of the symptoms of the illness. Such observations are further supported by the increase in the density of beta adrenoceptors on the lymphocytes of untreated depressed patients. As t he density of these receptors is normalized by effective antidepressant treatment, it has been postulated that changes in the beta receptor density may be a state marker of the condition. Other studies have shown that the elevation of growth hormone in the plasma following the administration of the alpha-2 adrenoceptor agonist clonidine is diminished in depressed patients, which suggests that central postsynaptic alpha-2 adrenoceptors are also subfunctional in such patients. This is perhaps the most consistent finding to have emerged in studies of the hypothalamic–pituitary axis in depression. As the clonidine response does not return to normal after effective antidepressant treatment, this is possibly a trait marker of depression. It should be emphasized that the reduced growth hormone response to clonidine cannot be accounted for by drug treatment, age or gender of the patient, which supports the view that the noradrenergic system is dysregulated in depression. Lastly, determination of the urine or plasma concentrations of MHPG (an indicator of central noradrenergic activity) suggests that central noradrenergic function is suboptimal in depression. Taken together, these results suggest that central noradrenergic function is decreased in depression, an event leading to the increase in the density of the postsynaptic beta adrenoceptors that show adaptive changes in response to the diminished synaptic concentration of the transmitter. It should be emphasized however that none of the studies of noradrenergic function in post-mortem material or tissues from depressed patients are entirely satisfactory. Many of the findings cannot be replicated, the number of patients studied is relatively small and the tritiated ligands used to determine the receptor density for example vary in their selectivity.
There is also evidence that the density of muscarinic receptors is increased in limbic regions of depressed patients who have committed suicide. If it is assumed that such a change reflects an increased activity of the cholinergic system, it could help to explain the reduced noradrenergic function as there is both clinical and experimental evidence to suggest that increased central cholinergic activity can precipitate depression and reduce noradrenergic activity. The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psychophysiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxyindole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2A receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. Thus platelets are, like neurons, of ectodermal origin and contain enzymes such as enolase that are otherwise restricted to neurons. In addition, platelets contain storage vesicles for 5-HT from which the amine is released by a calcium-dependent mechanism. An energy-dependent transport site for 5-HT also occurs on the platelet membrane, the structure of which is identical to that found on neurons in the brain. Furthermore, the platelet membrane contains 5-HT2A and alpha-2 adrenergic receptors that are functionally involved in platelet aggregation; there is evidence that the densities of these receptors are increased in depressed patients and largely normalized following effective treatment. Thus a number of important biochemical parameters may be determined from a platelet-rich plasma sample. It has been found, for example, that the transport of 3H-5-HT into the platelet is significantly reduced in the untreated depressed patient but largely returns to normal following effective treatment. This change occurs irrespective of the nature of the antidepressant used to treat the patient and may therefore be considered as a state marker of the illness. The function of the 5-HT2A receptor also appears to be subnormal in the untreated patient as shown by diminished aggregatory response to the addition of 5-HT in vitro, but normalizes when the patient recovers. As the number of 5-HT2A receptors on the platelet membrane of depressed patients is increased (as shown by the increased binding of a specific ligand such as 3H-ketanserin) this finding suggests that the G protein transducer mechanism, which links the receptor to the second messenger phosphatidyl inositol system within the platelet, is possibly defective in depression. There is also evidence that the modulatory site on the 5-HT transporter, the imipramine binding site, is decreased in depression, but unlike the changes in 5-HT uptake, remains unchanged by effective treatment. This suggests that the number of imipramine binding sites on the platelet membrane is a trait marker of the condition. However, the precise relevance of this finding is uncertain as the binding of the more specific ligand, 3H-paroxetine, is unchanged in depression. These studies of platelet function before, during and following treatment can give important information of the biochemical processes which may be causally related to depression. However, it is still uncertain how the changes in platelet function precisely reflect those occurring in the brain. Platelets are unconnected with the nervous system and therefore the changes observed could be a reflection of the hormonal changes (for example, glucocorticoids) that occur in depression. There is also evidence that some of the alterations in platelet function are a consequence of low molecular weight plasma factors that occur in the depressed patient and which are absent following effective antidepressant treatment.
Changes in brain and tissue amine neurotransmitters in depressed patients which may be indicative of the mechanism of action of antidepressants
. Evidence from the brains of depressed patients who committed suicide
. Increased density of beta adrenoceptors in cortical regions
. Increased density of 5-HT2A receptors in limbic regions
. Decreased concentration of 5-HIAA in several brain regions
. Increased muscarinic receptor density in limbic regions
Other clinical studies implicating an abnormal biogenic amine function in depression
. Decreased 5-HIAA concentration in CSF
. Decreased HVA (main dopamine metabolite) in CSF
. Decreased urinary excretion of the main central noradrenaline metabolite MHPG (?)
. Rapid relapse following administration of a tryptophan-free amino acid drink to depressed patients being treated with an SSRI
. Rapid relapse following administration of the tyrosine hydroxylase inhibitor alpha-methyl-tyrosine to depressed patients who respond to a noradrenaline reuptake inhibitor such as desipramine
While there has been considerable attention devoted to changes in noradrenergic and serotonergic function in depression, less attention has been paid to the possible involvement of dopamine in this disorder. This is surprising as anhedonia is a characteristic feature of major depression and a defect in dopaminergic function is thought to be causally involved in this symptom. Several studies have shown that the concentration of the main dopamine metabolite, homovanillic acid (HVA), is decreased in the CSF of depressed patients, particularly those with psychomotor retardation. These depressed patients who attempted suicide were also found to have a decreased urinary excretion of HVA and the second major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). It is of course possible that the dopamine deficit is more a reflection of the degree of retardation rather than the psychological state as similar changes in CSF HVA concentrations have been reported to occur in patients with Parkinson’s disease. This imp lies that the changes in the basal ganglia probably overshadow any changes in the mesolimbic dopaminergic system as the contribution of this area is relatively minor. With regard to the specific action of antidepressants on the dopaminergic system, there is evidence that buproprion (not marketed in most countries in Western Europe as an antidepressant but available in North America), amineptine and nomifensin (withdrawn because of the rare occurrence of haemolysis) owed their antidepressant efficacy to their ability to increase central dopaminergic function. There are also open label studies to suggest that the novel dopamine receptor agonist roxindole and the selective dopamine uptake inhibitor pramipexole may have antidepressant action. Thus when the results of the studies on platelets, lymphocytes, changes in cerebrospinal fluid metabolites of brain monoamines and the post-mortem studies are taken into account it may be concluded that a major abnormality in both noradrenergic and serotonergic function occu rs in depression, and that such changes could be causally related to the disease process.
Evidence from depressed patients
. Increased density of 5-HT2A receptors on the platelet membrane
. Decreased uptake of 3H-5-HT into platelet
. Increased beta adrenoceptor density on lymphocyte membrane
. Increased density of alpha-2 adrenoceptors on platelet membranes (*)
. Blunted growth hormone response to a clonidine challenge
. Blunted prolactin response to a fenfluramine challenge
Both clinical and experimental studies have shown that a number of transmitter receptors and amine transport processes show circadian changes. It is well established that depression is associated with a disruption of the circadian rhythm as shown by changes in a number of behavioural, autonomic and neuroendocrine aspects. One of the main consequences of effective treatment is a return of the circadian rhythm to normality. For example, it has been shown that the 5-HT uptake into the platelets of depressed patients is largely unchanged between 0600 and 1200 hours, whereas the 5-HT transport in control subjects shows a significant decrease over this period. The normal rhythm in 5-HT transport is only reestablished when the depressed patient responds to treatment. Thus it may be hypothesized that the mode of action of antidepressants is to normalize disrupted circadian rhythms. Only when the circadian rhythm has returned to normal can full clinical recovery be established. Chronobiological studies have shown tha circadian rhythms occur in the responsivity of animals to light, dark and psychotropic drugs. This implies that the timing of drug administration so that the drug reaches the target organ at its optimum sensitivity could help to improve its therapeutic efficiency. The results of experimental studies suggest that most antidepressants delay the circadian phase and lengthen the circadian period. These changes could be due to the drugs acting on the circadian pacemaker in the superchiasmatic nucleus. However, other brain regions could also be responsible together with antidepressantinduced changes in the retina which would lead to a modification of the processing of light stimuli; the lateral geniculate nucleus may also have a role to play. Seasonal affective disorder (SAD) generally consists of recurrent depressive episodes in autumn and winter that alternate with euthmia or hypomania in spring and summer. The seasonal rhythms of mood, sleep and weight change seen in SAD patients resemble hibernation seen in animals. This led to the hypothesis that extension of the photoperiod in winter could counteract the depressive symptoms. Exposure to bright light had indeed been shown to be efficacious. Clinical studies show that carbohydrate craving, a common feature of SAD, is possibly linked to a decreased serotonin turnover. Such a hypothesis is supported by the fact that the serotonin releasing agent D-fenfluramine is effective in treating SAD. Chronobiology is clearly an important area of research for the psychopharmacologist which needs more attention.
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). It is apparent that adaptational changes occur in adrenoceptors, serotonin, dopamine and 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.
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 supersensitivity 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 antidepressants cause adaptive changes in 5-HT1A, 5-HT2A alpha-1, alpha-2 and beta adrenoceptors, GABA-B receptors and possibly the NMDA-glutamate receptors.
Changes in cholinergic function
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 antidepressants, 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.
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