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APT (2000), vol. 6, p. 178 Advances in Psychiatric TreatmentLeonard (2000), vol. 6, pp. 178–186

Clinical implications of mechanisms of action of Brian Leonard

The purpose of this review is briefly to consider the (a) the precise diagnosis may be uncertain; biological basis of depression and to attempt to illus- (b) there is usually a considerable post-mortem trate how antidepressants produce their beneficial delay before the brain is removed at autopsy; effects by correcting these abnormalities. and (c) suicide is often committed by taking an overdose of together with , which grossly affects central monoamine Biochemical changes neurotransmitter function. in patients with depression Unless these variables are carefuly controlled, the and mechanisms of action value of results obtained from such analyses is uncertain. The neurotransmitter receptors in of drugs post-mortem brain are less labile than the neuro- transmitters that act upon them. The density of β-adrenoceptors is increased in cortical regions of In 1965, Schildkraut postulated that noradrenaline the brains from suicide victims who have suffered may play a pivotal role in the aetiology of depres- from depression. There is also an increase in the sion. In favour of this hypothesis was the obser- density of β-adrenoceptors on the lymphocytes of vation that the antihypertensive , untreated patients with depression. As the density which depletes central and peripheral vesicular of these receptors is normalised by effective stores of catecholamines such as noradrenaline, can antidepressant treatment, it has been postulated that precipitate depression in patients in remission. The changes in the β- density may be a state experimental drug α-methyl-paratyrosine that marker of the condition (Leonard, 1994a). blocks the synthesis of noradrenaline and Elevation of growth hormone in the plasma by inhibiting the rate-limiting enzyme following administration of the α2 adrenoceptor hydroxylase also precipitates depression in patients is diminished in patients with de- during remission. Such findings are only indirect pression, which suggests that central post-synaptic indicators that noradrenaline plays an important α2 adrenoceptors are also sub-functional in such role in human behaviour, and may be defective in patients. As the clonidine response does not return depression – more direct evidence is needed to to normal after effective antidepressant treatment, substantiate the hypothesis. The most obvious this is possibly a trait marker of depression. approach would be to determine the concentration In depression, it should be emphasised that the of noradrenaline and/or its major central metabolite reduced growth hormone response to clonidine 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cannot be accounted for by the drug treatment, age brains of suicide victims. The problem with such or gender of the patient, which supports the view post-mortem studies is that: that the noradrenergic system is dysregulated.

Brian E. Leonard obtained his PhD in neuropharmacology at the University of Birmingham in 1962 and his DSc from the National University of Ireland in 1976. His major research interest is in psychopharmacology. Since 1974 he has been Professor of Pharmacology at the National University of Ireland (Pharmacology Department, National University of Ireland, Galway, Ireland). Mechanisms of actions of antidepressants APT (2000), vol. 6, p. 179

the density of cortical 5-HT2a receptors in the brains Box 1. Changes in brain and tissue amine of suicide victims and also on the platelet membrane neurotransmitters in patients with depres- of patients with depression. sion which may be indicative of the Platelets are, like neurons, of ectodermal origin mechanism of action of antidepressants and contain enzymes such as enolase that are otherwise restricted to neurons. In addition, Evidence from the brains of patients with platelets contain storage vesicles for 5-HT, from depression who committed suicide which the amine is released by a calcium-dependent Increased density of β-adrenceptors in mechanism. An energy-dependent transport site for cortical regions 5-HT also occurs on the platelet membrane, the

Increased density of 5-HT2a receptors in structure of which is identical to that found on limbic regions neurons in the brain. Furthermore, the platelet Decreased concentration of 5-HIAA in α membrane contains 5-HT2a and 2 adrenergic several brain regions receptors that are functionally involved in platelet Increased muscarinic receptor density in aggregation; there is evidence that the densities of limbic regions these receptors are increased in patients with depression and largely normalised following effective treatment. The transport of 3H-5-HT into the platelet is significantly reduced in untreated patients with depression, but largely returns to Lastly, determination of the urine or plasma normal following effective treatment (Leonard, concentrations of MHPG (an indicator of central 1994b). This change, occurring irrespective of the noradrenergic activity), suggests that central nature of the antidepressant, may be a state marker noradrenergic function is sub-optimal in depression. of the illness.

Taken together, these results suggest that central The function of the 5-HT2a receptor appears sub- noradrenergic function is decreased in depression, normal in depression, as shown by diminished an event leading to an increase in the density of the aggregatory response to 5-HT in vitro, but normal- post-synaptic β-adrenoceptors (Leonard, 1986; ises when the patient recovers. The number of

Dinan, 1994). However, none of the studies of 5-HT2a receptors on the platelet membrane of patients noradrenergic function in post-mortem material or with depression is increased, a finding which tissues from patients with depression is entirely suggests that the G-protein and second messenger satisfactory. Many of the findings cannot be phosphatidyl inositol system is defective. Also, the replicated, the number of patients studied is modulatory site on the 5-HT transporter, the relatively small and the tritiated ligands used to binding site, is decreased in depression, determine the receptor density, for example, vary in but remains unchanged by effective treatment. This their selectivity. suggests that the number of imipramine binding sites The density of muscarinic receptors is also on the platelet membrane is a trait marker of the increased in limbic regions of patients with condition. However, the binding of the more specific depression who have commited suicide. If such a ligand, 3H-, is unchanged in depression. change reflects an increased activity of the It is uncertain how the changes in platelet function cholinergic system, it could reduce noradrenergic reflect those occurring in the brain. The changes function, as increased central cholinergic activity observed could be a reflection of the hormonal can precipitate depression and reduce noradrenergic changes (for example, glucocorticoids) that occur in activity (Janowsky et al, 1986). depression. Some of the alterations in platelet The role of (5-hydroxytryptamine, function are a consequence of low molecular weight 5-HT) has also been extensively studied in patients plasma factors that reduce following effective with depression. Whereas the overall psychophysio- antidepressant treatment (Nugent & Leonard, 1998). logical effects of noradrenaline in the central Patients undergoing treatment with selective nervous system appear to be linked to drive and serotonin reuptake inhibitors (SSRIs) rapidly relapse motivation, 5-HT is primarily involved in the when given an amino acid-containing drink that is expression of mood (see Charney et al, 1991). The deficient in (Delgado et al, 1990). The main 5-HT metabolite, 5-hydroxyindole acetic acid onset of the symptoms of depression is rapid (less (5-HIAA), is reduced in the cerebrospinal fluid (CSF) than 24 hours); the reduction in brain serotonin as a of patients with severe depression, as are 5-HT and consequence of the lack of tryptophan may be the 5-HIAA in the limbic regions of the brain of suicide cause of the altered mood state. However, those victims (Agren, 1980). Serotonin receptor function patients with depression in this study who is also abnormal in depression with an increase in responded to , which enhances APT (2000), vol. 6, p. 180 Leonard

degree of retardation rather than of the psycho- Box 2. Other clincial studies implicating an logical state, as similar changes in CSF HVA abnormal biogenic amine function in concentrations have been reported to occur in depression patients with Parkinson’s disease. Changes in the basal ganglia may overshadow any changes in the Decreased 5-HIAA concentration in CSF mesolimbic system, as the contrib- Decreased homovanillic acid (main dopamine ution of this area is relatively minor. metabolite) in CSF (not marketed in Europe but available Decreased urinary excretion of the main in North America) and nomifensin central noradrenaline metabolite MHPG(?) (withdrawn because of the rare occurrence of haemo- Rapid relapse following administration of a lytic anaemia) owed their antidepressant efficacy to tryptophan-free amino acid drink to their ability to increase central dopaminergic patients with depression being treated function. There are also open-label studies to suggest with an SSRI (?) that the novel agonist roxindole Rapid relapse following administration of the and the selective dopamine uptake inhibitor tyrosine hydroxylase inhibitor α-methyl- may have antidepressant action. tyrosine to patients with depression who respond to a noradrenaline such as desipramine Is there a common mechanism ?, finding equivocal of action?

Why is there a delay in onset of the antidepressant response? noradrenergic function, did not relapse when given the tryptophan-free drink. Some patients with Delay in onset of the therapeutic effect of anti- depression have a pronounced deficit in noradren- depressants, which clearly is unrelated to the acute ergic function rather than function, actions of these drugs on monoamine reuptake which may account for the differential response of transporters or monoamine oxidase, is probably some patients with depression to antidepressants related to the adaptive changes that occur in the that augment the serotonergic or noradrenergic pre- and post-synaptic receptors that govern system. neurotransmitter release. Antidepressant action usually has a gradual Dopaminergic function onset of over 2–3 weeks before the optimal effect is obtained (World Health Organization Mental Studies on platelets, lymphocytes, changes in Health Collaborating Centres, 1989). Much of the cerebrospinal fluid metabolites of brain mono- amines and post-mortem studies suggest that a major abnormality in both noradrenergic and serotonergic function occurs in depression, and that such changes could be causally related to the disease process. Box 3. Evidence from patients with Less attention has been paid to the possible depression involvement of dopamine in this disorder. However, Increased density of 5-HT receptors on the anhedonia is a characteristic feature of major 2a depression, and a defect in dopaminergic function platelet membrane 3 is thought to be causally involved in this symptom Decreased uptake of H-5-HT into platelet β (Willner, 1983). The concentration of the main Increased -adrenoceptor density on lympho- dopamine metabolite, homovanillic acid (HVA), is cyte membrane α decreased in the CSF of patients with depression, Increased density of 2 adrenoceptors on particularly those with psychomotor retardation. platelet membanes(?) Patients with depression who attempted suicide Blunted growth hormone response to a were also found to have a decreased urinary clonidine challenge excretion of HVA and the second major dopamine Blunted prolactin response to a metabolite, dihydroxyphenylacetic acid (DOPAC). challenge The dopamine deficit may be a reflection of the Mechanisms of actions of antidepressants APT (2000), vol. 6, p. 181

Box 4. Changes in neurotransmitter receptors that occur in the cortex of rat brain following chronic antidepressant treatment

Cortical β-adrenoceptors: decreased functional activity and density Cortical α1 adrenoceptors: increased density Cortical α2 autoreceptors: decreased functional activity Dopamine autoreceptors: decreased functional activity Cortical GABA-B receptors: decreased density

Limbic 5-HT1a receptors: increased density and decreased functional activity

Cortical 5-HT2a receptors: increased density and decreased functional activity

N.B. Most of these changes have been reported to occur with different classes of antidepressants but only following chronic treatment

early improvement is probably associated with a by the release of growth hormone (O’Keane et al, reduction in anxiety and improvement in sleep 1992). This suggests that the muscarinic receptors caused by the sedative action of the drugs. Delay in are supersensitive in patients with depression. onset of the therapeutic response cannot be easily Janowsky et al (1986) postulated that depression explained by the pharmacokinetic profile of the arises as the result of an imbalance between the drugs, as peak plasma (and presumably brain) central noradrenergic and cholinergic systems; in concentrations are usually reached in 7–10 days. depression, the activity of the former system is Furthermore, the 2- to 3-week delay is also seen in decreased and, conversely, in mania it is increased. many patients given electroconvulsive therapy As most antidepressants enhance noradrenergic (ECT). Box 4 summarises some of the changes in function, it is hypothesised that the reduction in neurotransmitter receptors that occur in the cortex cholinergic activity is a consequence of the increase of rat brain following ECT or the chronic admin- in noradrenergic activity. istration of antidepressants. Adaptational changes In summary, irrespective of the specificity of the occur in adrenoceptors, serotonin, dopamine and antidepressnts following their acute administration, type B γ-aminobutyric acid (GABA-B) receptors it can be speculated that a common feature of all of (Leonard, 1994a). 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 that facilitate central GABAergic transmission. A decrease in the activity Box 5. Changes in cholinergic and aminergic of GABA-B receptors may therefore contribute to the receptors in depression and following reduced central noradrenergic tone in depression. antidepressant treatment Evidence that central muscarinic receptors Changes in cholinergic function are supersensitive in patients with depression and that chronic antidepres- In the bulbectomised rat model of depression, a sant treatments normalise this super- decrease in cortical muscarinic receptors occurs that sensitvity. This effect does not depend on returns to control values following treatment with any intrinsic activity of the antidepressants (Earley et al, 1994). antidepressant (i.e. it is an indirect, The anticholinergic activity of the anti- adaptive effect) depressants is usually associated with their Following chronic administration to rats, unacceptable peripheral side-effects and most there is evidence that most antidepres- second-generation antidepressants lack such side- sants cause adapative changes in 5-HT1a, α α β effects. Possible support for a cholinergic hypothesis 5-HT2a, 1, 2 and -adrenoceptors, of depression is that the cholinesterase inhibitor GABA-B receptors and possibly the N- pyridostigmine, when administered to drug-free methyl-D-aspartate (NMDA)–glutamate patients with depression, causes an enhanced receptors activation of the anterior pituitary glands, as shown APT (2000), vol. 6, p. 182 Leonard these drugs is to correct the abnormality in Role of the glutamatergic system neurotransmitter receptor function. Such an effect in the action of antidepressants of chronic antidepressant treatment may parallel the time of onset of the therapeutic response. The glutamatergic system is the main excitatory neurotransmitter pathway in the brain. Tricyclic Link between the serotonergic antidepresssants (TCAs) inhibit the binding of and noradrenergic systems dizolcipine to the ion channel of the main glutamate receptor, the NMDA-receptor in the brain (Reynolds Chronic administration of antidepressants enhances & Miller, 1988). Newer antidepressants have a the inhibitory response of forebrain neurons qualitatively similar effect (Kitayama et al, 1997). to microiontophoretically applied 5-HT. This Whether this is due to direct action on glutamate enhanced response is blocked by lesions of the receptor sites or indirect action via the glycine noradrenergic projections to the cortex. This dual receptor site is uncertain. Glycine and drugs effect could help to explain enhanced serotonergic modulating the glycine site show antidepressant- function that arises after chronic administration of like activity in animal models of depression. Thus, antidepressants or ECT. Conversely, impairment of antidepressants may act as functional NMDA serotonergic function by means of selective neuro- receptor antagonists. toxins (e.g. 5,7-dihydroxytryptamine) or a 5-HT synthesis inhibitor (e.g. parachlorophenylalanine) Intracellular changes that occur largely prevents the decrease in functional activity β following chronic antidepressant of cortical -adrenoceptors that usually arises treatment following chronic antidepressant treatment. 5-HT1b receptors are located on serotonergic nerve terminals and act as autoreceptors; stimulation by serotonin The coupling of the NDMA-receptor on the cell decreases the further release of this amine. Chronic surface to the intracellular second messenger is administration of selective SSRIs slowly desensitises brought about by a member of the G-protein family. the inhibitory 5-HT1b autoreceptors and thereby enhances serotonin release.

Likewise, the 5-HT1a somatodendritic receptors inhibit the release of serotonin and it is posulated that the enhanced release of the transmitter following Box 6. Mechanism of action of antidepres- chronic administration of SSRIs is a consequence of sants: changes in serotonergic function adaptive down-regulation of the inhibitory 5-HT1a receptors (Blier et al, 1990). The validity of this There is experimental evidence that the hypothesis is supported by the pharmacological chronic administration of antidepressants or ECT enhances the inhibitory effect of effect of 5-HT1a antagonists. Thus, the beta-blocker microiontophoretically applied 5-HT. This and 5-HT1a antagonist , in combination with or paroxetine, may enhance the effect is blocked by lesions of the norad- therapeutic efficacy of the SSRI and, in some studies, renergic projections to the frontal cortex reduce the time to onset of the peak therapeutic effect SSRIs after chronic administration down-

(Tome et al, 1997). However, several investigators regulate the inhibitory 5-HT1a receptors on have not been able to replicate such findings (see the serotonergic cell body, thereby leading McAskill et al, 1998). to an enhanced release of the transmitter Serotonin can also regulate dopamine turnover. from the nerve terminal A positive correlation exists in patients with Serotonin can also decrease dopamine depression between the HVA and 5-HIAA concen- release from the substantia nigra (an trations in the CSF (Agren, 1980). Stimulation of the important dopaminergic nucleus). This 5-HT cell bodies in the median raphe causes may account for the observation that some reduced firing of the substantia nigra, where SSRIs cause dystonias and precipitate the dopamine is the main neurotransmitter. Serotonin symptoms of parkinsonism if given to such plays an important role in modulating dopaminergic patients who are responding to L-dopa. function in many regions of the brain, including the appears to differ from other mesolimbic system. The effects of some antidepres- SSRIs in this respect and may slightly sants that show an apparent selectivity for the enhance dopaminergic function by serotonergic system could be ascribed to secondary reducing reuptake of this transmitter changes in dopaminergic pathways. Mechanisms of actions of antidepressants APT (2000), vol. 6, p. 183

Beta-adrenoceptors are linked to adenylate cyclase and, depending on the subtype of receptors, 5-HT is Box 7. Possible role of excitatory amino linked to either adenylate cyclase (5-HT1a, 5-HT1b) acids and intracellular second messengers or phospholipase (5-HT2a, 5-HT2c). Activation of in the action of antidepressants phospholipase results in an intracellular increase in the secondary messengers diacylglycerol and In experimental studies, chronic antidepres- inositol triphosphate (IP3), the IP3 then mobilising sant treatments have been shown to intraneuronal calcium. reduce the behavioural effects of the The net result of the activation of the secondary NMDA-glutamate messenger systems is to increase the activity of the dizolcipine. This suggests that antidepres- various intracellular protein kinases (termed third sants may act as functional NMDA receptor messengers) that phosphorylate cell proteins to antagonists and thereby reduce excitatory produce a physiological response. Racagni et al glutamate transmission that is mediated (1991) have investigated the effect of chronic by NMDA receptors antidepressant treatment on the phosphorylation Intracellular protein phosphorylation is of proteins associated with the cytoskeletal structure enhanced by chronic antidepressant treat- of the nerve cell. Antidepressants could affect the ment. This leads to the increased synthesis function of the cytoskeleton by changing the of microtubules that form an important component of the associated protein phosphory- feature of the cellular cytoskeleton. Thus, lation system. Thus, both typical (e.g. desipramine) antidepressants might change signal and atypical antidepressants (e.g. (+), transduction within the neuron a specific noradrenaline reuptake inhibitor, and Enhanced synthesis and transport of neuro- fluoxetine, an SSRI) increased the synthesis of a transmitter-synthesising enzymes (e.g. microtubule fraction. These changes occurred only tyrosine and tryptophan hydroxylase) after chronic antidepressant treatments. Antidepres- sants might thereby change neuronal signal transduction processes distal to the receptor. Glucocorticoid receptors: increase the negative feedback mechanism and adaptive changes following thereby reduce the release of cortisol. In support of this hypothesis, there is preliminary clinical antidepressant treatment evidence that metyrapone (and the steroid synthesis inhibitor ketoconazole) may have antidepressant Glucocorticoid receptors have been identified in the effects. Recently, several lipophilic antagonists of nuclei of catecholamine and 5-HT-containing cell corticorophin-releasing factor (CRF) type 1 receptor, bodies in the brain. Glucocorticoid receptors activate which appears to be hyperactive in the brain of deoxyribonucleic acid-binding proteins, which can patients with depression, have been shown to be modify the transcription of genes. Chronic adminis- active in animal models of depression. Clearly, this tration of imipramine increases glucocorticoid is a potentially important area for antidepressant receptors in rat brain, particularly the noradrenergic development (Mansbach et al, 1997). and serotonergic cell body regions. Glucocorticoid receptors are present in high Lymphocyte glucocorticoid receptors are sub- density in the amygdala, and neuroimaging studies sensitive in patients with depression. The failure of have shown that the amygdala is the only structure the negative feedback mechanism that regulates the in which the regional blood flow and glucose secretion of adrenal glucocorticoids further suggests metabolism consistently correlate positively with the that the central glucocorticoid receptors are sub- severity of depression (Lesser et al, 1994). This sensitive. Hypersecretion of cortisol is a character- hypermetabolism appears to reflect an underlying istic feature of many patients with major depression pathological process as it also occurs in asymptom- (Dinan, 1994). Central neurotransmission occurring atic patients and in the close relatives of patients. in depression may, in part, result from the effects of chronic glucocorticoids. Glucorticoid synthesis inhibitors (e.g. metyrapone) Effects of antidepressants may be able to reduce the abnormality in neuro- on endocrine–immune functions transmitter function by decreasing the cortisol concentration. Stress is frequently a trigger factor for depression in Typical antidepressants increase the density of vulnerable patients. Corticorophin-releasing factor glucocorticoid receptors in rats. Such an effect could is elevated in the CSF of untreated patients with APT (2000), vol. 6, p. 184 Leonard depression, which presumably leads to the hyper- Antidepressants and changes cortisolaemia that usually accompanies the in neuronal structure condition. One of the consequences of elevated plasma glucocorticoids is a suppression of some aspects of cellular immunity. Many aspects of both Another possible mechanism whereby antidepres- cellular (for example, natural killer cell activity, T- sants may change the physical relationship between cell replication) and non-cellular (for example, raised neurons in the the brain is by inhibiting neurite acute phase proteins) immunity are abnormal in un- outgrowth from nerve cells. inhibits treated patients with depression (see Song & Leonard, neurite outgrowth from chick embryonic cerebral 1995). This may contribute to the susceptibility of explants in vivo (Wong et al, 1991). A common mode patients with depression to physical ill health. of action of all antidepressants could be to modify A link between CRF, the cytokines that orchestrate the actual structure of nerve cells and possibly many aspects of cellular immunity and the prostaglan- eliminate inappropriate synaptic contacts that are dins of the E series has been the subject of consid- responsible for behavioural and psychological erable research in recent years. Prostaglandin E2 changes associated with depression. (PGE2) concentrations are raised in the plasma of It is also possible that chronic antidepressant untreated patients with depression and are treatment may affect pathways that involve receptor normalised following effective treatment with TCAs. interactions with protein tyrosine kinases, by Raised PGE2 concentrations reflect increased pro- increasing specific growth factor synthesis or by inflammatory cytokines (particularly interleukins 1 regulating the activity of proinflammatory cytokines and 6 and tumour necrosis factor, ), which occur as (Duman et al, 1997). These pathways control many a consequence of increased macrophage activity in aspects of neuronal function that ultimately underlie the blood and brain. In the brain, the microglia the ability of the brain to adapt and respond to function as macrophages and produce such cytokines environmental stimuli. The infusion of one of these locally. Thus, the increased synthesis of PGE2 may transcription factors (brain-derived neutrophic contribute to the reduction in amine release in the factor) into the mid-brain of rats results in brain that appears to underly the pathology of antidepressant-like activity (Siuciak et al, 1996), an depression. It has recently been postulated that anti- action associated with an increase in the synthesis depressants normalise central neurotransmission of tryptophan hydroxylase, the rate limiting enzyme by reducing brain concentrations of both the cyto- in the synthesis of serotonin. kines and PGE2 by inhibiting central and peripheral macrophage activity together with cyclooxygenase type 2 activity in the brain. Cyclooxygenase is the Conclusions key enzyme in the synthesis of the prostaglandins. The usefulness of TCAs in severe rheumatoid arthritis may reflect the inhibitory action of such drugs on cyclo- Circumstantial evidence from the body fluids of oxygenase activity. These effects of TCAs, together patients, and from the brains of suicide victims who with those in glucocorticoid receptor function, may suffered from depression, indicate an abnormality thus normalise defective central neurotransmission.

Box 9. The possible role of prostaglandins and cytokines in depression Box 8. Role of glucocorticoids in modulating brain amines in depression There is evidence that both cellular and non- cellular immunity are abnormal in patients Glucocorticoid receptors occur on catechol- with depression. The proinflammatory amine- and 5-HT-containing cell bodies in cytokines (interleukins 1 and 6 and the brain. There is evidence that the tumour necrosis factor alpha) from macro- glucocorticoid receptors are hyposensitive phages are raised in depression. This leads in patients with depression. Chronic to increased prostaglandin E2 synthesis antidepressant treatment sensitises these and release, which may lead to a reduction receptors, thereby normalising the nor- in central monoamine release. Chronic adrenergic and serotonergic function that antidepressant treatments reduce both the is reduced by hypercortisolaemia, which proinflammatory cytokines and prosta- occurs in major depression glandin E2 Mechanisms of actions of antidepressants APT (2000), vol. 6, p. 185

in serotonergic and noradrenergic function (together depletion of plasma tryptophan. Archives of General Psychiatry, 47, 411–418. with changes in other transmitters such as acetyl- Dinan, T. G. (1994). Glucocorticoids and the genesis of choline and GABA). Such changes in amine depressive illness. A psychobiological model. British Journal neurotransmitter function generally normalise of Psychiatry, 164, 365–371. Drevets, W. C. (1998) Functional neuroimaging studies of following effective antidepressant treatment. It is depression: the anatomy of melancholia. Annual Review of postulated that all types of antidepressants and ECT, Medicine, 49, 341–361. irrespective of their presumed specificity for acting Duman, R. S., Henninger, G. R. & Nestler, E. J. (1997) A molecular and cellular theory of depression. Archives of on a particular neurotransmitter system, ultimately General Psychiatry, 54, 597–606. correct the multitude of neurotransmitter abnor- Earley, B., Glennon, M., Lally, M., et al (1994) Autoradio- malities that cause depression. graphic distribution of cholinergic nuscarinic receptors and serotonin2 receptors in olfactory bulbectomized (OB) rats My personal view is that these changes in after chronic treatment with and desipramine. neutrotransmitters, which may be causally connec- Human Psychopharmacology, 9, 397–407. ted to the symptoms of depression, are secondary to Janowsky, D. S., Risch, S. C., Kennedy, B., et al (1986) Central muscarinic effects of physostigmine on mood, cardiovas- those involving hyposensitive central glucocorticoid cular function, pituitary and adrenal neuroendocrine receptors, proinflammatory cytokines and an release. Psychopharmacology, 89, 150–154. increase in prostaglandin E2 (both centrally and Kitayama, I., Yaga, T., Kayahara, T. J., et al (1997) Long- term stress degenerates, but imipramine regenerates, peripherally), together with changes in the structure noradrenergic axons in the rat cerebral cortex. Biological of neurons. Thus, factors such as the duration of Psychiatry, 42, 687–696. antidepressant treatment and delay in onset of the Leonard, B. E. (1986) Neurotransmitter receptors, endocrine response and the biological substrates of depression: a clinical response may reflect the subcellular review. Human Psychopharmacology, 1, 3–18. adaptive changes that underlie the mechanism of ––– (1994a) Biological strategies for the development of action of these drugs. antidepressants. CNS Drugs, 1, 285–304. ––– (1994b) Effect of antidepressants on specific neurotrans- mitters: are such effects relevant to their therapeutic action? In Handbook of Depression and Anxiety – A Biological References Approach (eds J. A. den Boer & J. M. A. Sitzen), pp. 379– 404. New York: Marcel Dekker. Lesser, I. M., Mena, I. & Boone K. B. (1994) Reduction of Agren, H. (1980) Symptom patterns in unipolar and bipolar cerebral blood flow in older depressed patients. Archives depression correlating with monoamine metabolities in in General Psychiatry, 51, 677–686. the cerebrospinal fluid: II. Suicide. Psychiatric Research, 3, Mansbach, R. S., Brooks, E. N. & Chen, Y. L. (1997) 225–236. Antidepressant-like effects of CP-154, 526, a selective CRF Blier, P., de Montigny, C. & Chaput, Y. (1990) A role for the receptor antagonist. European Journal of Pharmacology, 323, serotonin system in the mechanism of action of antidepres- 21–26. sant treatments: preclinical evidence. Journal of Clinical McAskill, R., Mir, S. & Taylor, D. (1998) Pindolol augmen- Psychiatry, 51, 14–20. tation of antidepressant therapy. British Journal of Charney, D. S., Delgado, P. L., Price, L. H., et al (1991) The Psychiatry, 173, 203–208. receptor sensitivity hypothesis of antidepressant action. In Nugent, D. F. & Leonard, B. E. (1998) Platelet abnormalities The Role of Serotonin in Psychiatric Disorders (eds S.-L. Brown in depression. Journal of Serotonin Research, 4, 251–266. & H. M. van Praag), pp. 27–56. New York: Brunner/Mazel. O’Keane, V., O’Flynn, K., Lucey. J., et al (1992) Pyridostigmine Delgado P. L., Charney, D. S., Price, L. H., et al (1990) Serotonin induced growth hormone responses in healthy and function and the mechanism of antidepressant action. depressed subjects – evidence for cholinergic supersen- Reversal of antidepressant induced remission by rapid sitivity in depression. Psychological Medicine, 22, 55–60. Racagni, G., Tinelli, D. & Bianchi, E. (1991) cAMP dependent binding proteins and endogneous phosphorylation after antidepressant treatment. In Hydroxytryptamine in Psychiatry (eds M. Sandler, A. Coppen & S. Hartnet) (5th edn), pp. 116–123. Oxford: Oxford Medical Publications. Reynolds, I. J. & Miller, R. J. (1988) Tricyclic antidepressants Box 10. Changes in neuronal structure in block N-methyl-D-aspartate receptor: similarities to the action of zinc. British Journal of Pharmacology, 95, 95–102. depression Siuciak, J. A., Lewis, D., Wiegand, S. J., et al (1996) Antidepressant like effect of brain derived neutrophic There is evidence that inadequately treated factor. Pharmacology, Biochemistry and Behavior, 56, 131– 137. or untreated major depression is associ- Song, C. & Leonard, B. E. (1995) The effect of olfactory ated with a decrease in hippocampal bulbectomy in the rat, alone or in combination with volume. This could be a consequence of antidepressants on immune function. Human Psycho- pharmacology, 10, 7–18. the increase in proinflammatory cytokines Tome, M. B., Isaac M. T., Harte, R., et al (1997) Paroxetine and hypercortisolaemia and pindolol: a randomized trial of serotonergic autorecep- Experimental evidence suggests that chronic tor blockade in the reduction of antidepressant latency. International Clinical Psychopharmacology, 12, 81–89. antidepressant treatments increase the World Health Organization Mental Health Collaborating formation of transcription factors within Centres (1989) Pharmacotherapy of depressive disorders: the brain, which increases neuronal a consensus statement. Journal of Affective Disorders, 17, 197–198. plasticity and leads to recovery Wong, K. L., Bruch, R. C. & Farbman, A. I. (1991) Amitriptyline-mediated inhibition of neurite outgrowth APT (2000), vol. 6, p. 186 Leonard

from chick embryonic cerebral explants involves a 3. The following mechanisms have been postulated reduction in adenylate cyclase activity. Journal of Neurochemistry, 57, 1223–1230. to account for the therapeutic action of anti- Willner, P. (1983) A conceptual framework for psycho- depressants following their chronic administration: biological synthesis. Biological Psychiatry, 18, 1447–1450. a decreased density (down-regulation) of cortical β-adrenoceptors b increased density (up-regulation) of Multiple choice questions cortical β-adrenoceptors c decreased density of α2 (inhibitory) adrenoceptors in limbic regions of the brain

d desentitisation of inhibitory 5-HT1b 1. Compared with controls, the following have been receptors in limbic regions of the brain. suggested as biological markers of depression: a reduced plasma cortisol after 1 mg dexameth- asone treatment b reduced growth hormone secretion after clonidine treatment c reduced prolactin secretion after fenfluramine treatment d decreased 5-HIAA concentration in the CSF. MCQ answers 2. The following changes have been reported to occur on platelet membranes of patients with depression: 123 a increased 3H-paroxetine binding to the 5-HT aF aF a T transporter bT bT b F b decreased 3H-imipranine binding to the cT cF c T 5-HT transporter dT dF d T c increased density of β-adrenoceptors eF eF e F

d decreased density of 5-HT2a receptors.

American Psychiatric Association Annual Meeting 13–17 May 2000 Chicago

The Royal College of Psychiatrists and BMJ Publishing will be promoting their books and journals together at this important congress. The on-line versions of the three College journals, British Journal of Psychiatry, Advances in Psychiatric Treatment and Psychiatric Bulletin, will be launched at this meeting. The journal Evidence-Based Mental Health is currently available on-line and will also be demonstrated during the congress.

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