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2000 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2000 Volume 4 Pages 281 ± 286
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Depression therapy: Future prospects MICHAEL BERK
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Department of Psychiatry, University of the Witwatersrand, South Africa Correspondence Address Dr M Berk, Department of Psychiatry, University of the Witwatersrand Medical School, 7 York Road, Parktown, South Africa, 2193 Tel: 27-11-647 2026 E-mail: [email protected]
Received 15 April 1999; Revised 5 April 2000; Accepted 1 June 2000
Current biological approaches to the treatment of depression focus mainly on modification of monoaminer gic neurotransmission. New agents targeting these neurotransmitters are under developmen t. Many novel antidepressan t targets are however under investigation. These include the neurokinins, glutamate , purinoceptors, opioids and trophic factors. While many of these potential targets are likely to fail clinical developmen t, exciting novel therapeutic options are likely to emerge. (Int J Psych Clin Pract 2000; 4: 281 ± 286) Keywords depression glutamate receptors opioids dopamine
INTRODUCTION
T
he discovery of antidepressan t action was initially accidental, as, for example, with iproniazid, an anti-tuberculo us agent found to have antidepressan t activity. Many tricyclics, initially developed as antihistamines, were similarly found to have antidepressan t efficacy. The second phase of development was marked by the identificatio n of the antidepressa nt mechanisms of action, such as MAO inhibition and re-uptake inhibition, and led to the development of specific agents such as fluoxetine . In the third phase, in which we are currently, agents which combine multiple identified monoaminerg ic mechanisms are being developed. Examples of this group include venlafaxine , a serotonin and noradrenalin e (and to a lesser extent, dopamine) re-uptake inhibitor, nefazodone, a 5HT2 antagonist and weak 5HT re-uptake inhibitor, and mirtazapine, an alpha-2 antagonist and 5HT2 and 5HT3 antagonist.1 The promise of higher response rates in this group has not really been fulfilled . The safety issues that limited the first generation of antidepressan ts had been largely solved by the newer agents. Nevertheless , significan t challenges remain. All current agents are still targeting the same monoamine transmitters, albeit through different mechanisms . No agent has broken the 60 ± 70% response rate barrier. Adverse events remain an issue; anticholinerg ic side-effect s have simply been replaced by sexual dysfunction , which has (for example) been replaced by weight gain. Despite much marketing mileage suggesting the contrary, speed of response remains largely unaltered through the generations of drugs (Table 1).2
neurokinins purinoceptors neurotrophins serotonin
An interesting trend, mirroring the development of agents with multiple mechanisms of action, is a return to a more targeted polypharmac y where antidepressan ts with complementary mechanisms of action are combined, particularl y in refractory cases. Of perhaps the greatest interest, however, is the development of agents with entirely novel mechanisms of action, targeting transmitters such as substance P, encephalins and N-methyl-D-as partate (NMDA). It is however likely that very few hypotheses will translate into successfu l agents. Many methodologica l pitfalls exist in the development of novel agents. The screening of new agents uses animal models of depression , such as the forced swimming test. There is a real risk that tests validated using older agents may not be sensitive to novel mechanisms of action.3 A current issue in clinical trials is the very high placebo response rates in many outpatient trials, which has seen the demise of many promising agents. This has led to an increased focus on antidepressa nt trial design and patient selection.4 ,5 Papers for this review were identified by MEDLINE searches using multiple keywords. Due to the massive numbers of citations available, papers of arbitrary clinical interest were selected for review.
FUTURE POSSIBILITIES MONOAMINES Many novel approaches to the development of antidepressant therapies are under development . Novel monoaminergic mechanisms of action, involving for example the 5HT6 and 5HT7 receptors, are under investigation . It is of
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ties.1 9 Pramipexole , a dopamine agonist, shows eficacy in animal models.2 0
Table 1 Antidepressant classification First generation Second generation Third generation
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Fourth generation
Accidentally dirty ± tricyclic agents Deliberately clean ± the selective agents Deliberately dirty ± multiple monoaminergic mechanisms of action Novel mechanisms and neurotransmitters
interest that certain established antidepressan ts, such as clomipramine , amitriptyline , mianseri n and clozapine , have been shown to have activity at the 5HT6 and 5HT7 receptor. 6 ,7 Attempts to combine serotonin re-uptake inhibition (SSRI) with other mechanisms are under development , and include LY 233708, which is an SSRI with 5HT1 A properties, and litoxetine, an SSRI with 5HT3 properties.8 Most drugs exist as a mixture of racemic forms. Chirally different forms often have pharmacodyn amic and pharmacokinetic differences . Chirally pure drugs may differ from mixed forms in ways that may translate into a clinicall y meaningful advantage. Fluoxetine, for example, exists as Rand S-enantiomers . R-fluoxetine may have enhanced activity at 5HT2 A and 5HT2 C receptors compared to Sfluoxetine, and have no active metabolites.9 ,1 0. Similarly, the pharmacologi cal activity of citalopram may lie in its S+ enantiomer.1 1 SSRIs initially cause an attenuated firing of 5HT neurons, due to 5HT1 A somatodendrit ic agonism. As 5HT1 A receptors downregulate , the firing rate again increases, which correlates with the clinical response . The possibilit y that prevention of initial suppressio n could speed up response has been investigated.1 2 Pindolol is a beta-blocker and 5HT1 A antagonist. There is some evidence of enhanced speed of action when pindolol is used together with SSRIs, and possibly greater response ratest. The data however are currently equivocal , with encouraging openlabel studies not being fully supported by controlled data. 1 3 ± 1 5 Dopamine is a neglected monoamine, and many agents with dopaminergi c properties are definitely efficacious in depression . The MAO inhibitors amphetamin e and nomifensine are effective antidepressa nt agents with prominent dopaminergi c properties. There is concern regarding the risks of dependance, particularl y with dopamine-rel easing agents, and of the potential of all dopaminergi c agents for aggravatio n of psychosis . Amineptine and medifoxami ne are dopamine re-uptake inhibitors that have potential antidepressan t efficacy.7 ,1 6 Lisuride is a dopamine and serotonin agonist under development which has affinity for 5HT6 and 5HT7 receptors. 1 7 Dopamine antagonists such as sulpiride 1 8 and olanzapine may have antidepressan t proper-
SUBSTANCE P Substance P (SP), also known as neurokinin-1 , is the most widespread neurokinin in the central nervous system. It is found particularly in brain areas, mediating stress and affective response . In addition, noradrenalin e- and 5HTcontaining neurons often co-express SP. Conventional antidepressa nts are known to downregulat e SP synthesis. Substance P antagonists are under development , and preclinica l assays of antidepressa nt activity have shown the SP antagonist MK 869 to be positive. A phase-2 randomized placebo- controlled double-blin d trial was positive, but a subsequent trial reported negative results. There appears to be a dose-respons e relationship with SP antagonists. More potent SP antagonists are in development. 2 1 ,22
OPIOIDS; MELATONIN The opioids include the encephalins , dynorphins and endorphins . They have long been known to modulate mood. The opioidergi c system may be involved in the antinociceptive effects of the antidepressa nts.2 3 Preclinical studies of an encephalinas e inhibitor, BL-2401, show anti-nocicept ive and antidepressan t effects.2 4 RB 101, an inhibitor of encephali n catabolism, also has antidepressa nt effects in preclinica l models.2 5 Melatonin is a neurohormon e, whose major known role is in circadian rhythms. Depression is a documented sideeffect of melatonin. A melatonin agonist, S20304, demonstrates evidence of antidepressa nt efficacy with chronic administratio n in animal models.2 6 Preliminar y open-label studies present conflicting evidence on the use of melatonin in depression .2 7 ,28 A role in seasonal patterns of depressio n is provisionall y suggested. It is possible that the effect of melatonin on mood may be mediated via 5HT2 a receptors. 2 9
SECOND MESSENGERS, NITRIC OXIDE Most antidepressa nts indirectly affect second messengers , and lithium has direct effects on second messenger systems. Chronic administratio n of antidepressan ts upregulates the cyclic adenosine monophospha te pathway at many levels, including increased expression of the cAMP response-ele ment-binding protein (CREB).3 0 Forskoli n and NKH477 are agents that elevate the cyclic AMP cascade, and both show in vivo antidepressan t efficacy.3 1 Rolipram is a phosphodiest erase inhibitor that increases cAMP. Initial positive trials were however followed by disappointin g results. 3 2 Nitric oxide (NO) is a free gas that is synthesized from arginine by NO synthase and diffuse s into adjacent cells, where it binds to many targets including activating guanyl
Depression therapy: Future prospects
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cyclase and increasing cyclic guanosine monophospha te. Carbon monoxide may also be a neurotransmi tter with NMDA effects. Nitric oxide interacts with glutamate (NMDA), opioid and glucocorticoi d pathways. There is some evidence that antidepressan t anti-nocicepti ve activity may be mediated by nitric oxide.3 3 Methylene blue inhibits nitric oxide synthase and has antidepressan t and antianxiety effects in animal models.3 4 Nitric oxide has a role in sexual function, particularl y in smooth muscle relaxation.3 5 Sildenafil , which potentiates nitric-oxide- mediated smooth muscle relaxation,3 6 may have a role in antidepressa ntinduced sexual dysfunction .3 7 ,38
CYTOKINES There is increasing evidence that depression may be an inflammatory disease. Depression has long been associated with impaired immune function. Recently, immunologic al activation has been recognized, with increased levels of cytokines such as interleukins , complement and interferon reported in some studies.3 9 Neurotransmi tters such as serotonin and the immune system interact with each other. Serotonin modulates lymphocyte proliferatio n and natural killer cell activity. Anti-serotonin and anti-serotonin receptor antibodies have been found in depressiontc . In addition, cytokines are reported to raise NA and 5HT turnover. 4 0 Healthy patients given cytokines develop depressive symptoms.4 1 Depression is far more common in autoimmune and inflammator y diseases such as multiple sclerosis and systemic lupus erythematosis than in the general population.4 2 Women, who have higher rates of mood disorder, have higher cytokine levels, especially during the postpartum period, the highest risk period for the development of mood disorder.4 3 There is some evidence that stress-induc ed cytokine secretion may cause depressive symptoms. Established antidepressa nts such as clomipramine , citalopram and imipramine inhibit cytokine release. 4 4 Interleukin- 1 receptor antagonists prevent the development of learned helplessnes s in rats.4 5 ,4 6
ANGIOTENSIN, GLUCOCORTICOIDS Many cardiac drugs are capable of aggravating mood symptoms. Angiotensin may be involved in mood regulation. The angiotensin-c onverting enzyme inhibitor captopril is reported to show antidepressa nt properties. The drug is positive in animal screening tests. Comparative trials against enalapril show that captopril has an advantage in quality of life, a measure containing many mood variables. However, no formal clinical trials in depression have been done. Captopril may nevertheless be seen as a first-line antihypertens ive in depressed patients.4 7 ,48 Glucocorticoi ds are one of the oldest hormones that have been documented as being altered in depression . Elevated adrenocortico trophic hormone (ACTH) and cortisol activity, as well as Dexamethaso ne suppressio n test non-suppres sion, have long been shown in depression .
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In open trials for resistant depression , glucocorticoi d antagonists, including ketoconazole , amino glutethamide, and metapyrone, have been reported to be efficacious .4 9 Ketoconazole has been found to be of value in depressed patients with raised cortisol levels;5 0 controlled data is however lacking. A corticotrophin-releasing factor (CRF) antagonist, CP-154,526, has been shown to be positive in animal models of depression .5 1
GLUTAMATE Glutamate receptors, particularly the NMDA subtype, may have a role in depression . Supersensiti ve platelet NMDA receptors are found in depression with psychotic features,5 2 as well as in non-psychot ic depression (Berk et al, unpublished ). Imipramine has been shown to have NMDA effects. The NMDA antagonist MK 801 has been shown to be positive in animal models, although tolerability issues preclude its use in clinical practice.5 3 ,5 4 It is well established that NMDA antagonists such as phencyclidi ne can cause psychosis. 5 5
PURINOCEPTORS Purinoceptor s, particularly the adenosine receptor, have been examined in depression . Adenosine is a prototypic neuromodula tor. Theophyllin e and caffeine are antagonists at purinoceptor P1 receptors, and can cause anxiety. Tricyclic antidepressan ts are known to inhibit adenosine re-uptake and potentiate actions of adenosine. Blunted adenosine platelet A2a receptor function is reported in depression.5 6 Electroconvul sive therapy upregulates A1 (a subclass of the P1 receptor). Adenosine A1 and A2a antagonists showed antidepressa nt effects in animal models but were withdrawn from clinical trials.5 7 ,58
NEUROTROPHINS The neurotrophins are another novel antidepressa nt target. Brain-derive d neurotrophic factor (BDNF) promotes function, sprouting and regrowth of neurons. Infusions of BDNF show antidepressan t effects in animal models.5 9 Stress has been shown to decrease BDNF, and certain antidepressa nts may increase BDNF. Neurotrophin stimulants may be promising antidepressan t targets6 0
HYPERICUM Herbal remedies such as Hypericum (St John’s wort) have gained widespread popular acceptance, with modest evidence of efficacy and minimal safety data. Hypericum appears to contain many active compounds. The mechanism of action of hypericum is unclear, with reported pharmacolog ical properties including monoaminer gic reuptake inhibition , GABA agonism, MAO blockade, sigma affinity, and muscarinic anticholiner gic affinity.6 1 ± 6 4 There is some evidence that hypericum is superior to placebo and
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as effective as standard antidepressa nts in mild to moderate depression , although some studies had methodological limitations.6 5 ,6 6 There are some concerns regarding drug interactions with anaesthetic agents and other serotonergi c antidepressan ts. Much additional data is necessary before hypericum is established in terms of efficacy and safety.
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TRANSCRANIAL MAGNETIC STIMULATION Transcrania l Magnetic Stimulation (TMS) is an experimental therapeutic modality. Magnetic fields may alter mood and anxiety. Experimental studies have shown that magnetic stimulation can cause downregulat ion of the 5HT1 B receptor. Like ECT, TMS can activate immediate early genes. Left prefrontal TMS has been shown by positron emission tomography (PET) to increase 1 8 Ffluorodeoxyg lucose uptake. Antidepressa nt effects of left prefrontal TMS at high (20 Hz) frequency, but not of right prefrontal TMS, have been reported. Younger, right-handed patients are more likely to respond. Gabapentin may enhance the therapeutic response to TMS. Right prefrontal TMS may possibly be antimanic.6 7 ± 7 1 Controlled data on the short-term use of TMS in recurrent depression are now available. 7 2
focussed approach to the development of novel therapeutic approaches. It is thus of clinical importance to focus research on markers of physiologica l disturbance outside the monoamines . It is clear that depression involves a far wider net than the monoamines ; however, what is at issue is which of these changes are core changes and which are ripple effects. The currently available supply of drugs for depressio n targets a small number of the systems shown to be involved. In conclusion, many avenues are open for study. These include modification of existing techniques and mechanisms, as well as the development of novel mechanisms and targets. While most of these novel targets are not likely to yield clinically useful results, the development of exciting new therapies is inevitable.
KEY POINTS
· · ·
CONCLUSION Advances in the understandi ng of the neurobiologi cal changes in major depressio n should lead to a more
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Current treatment of depression focuses mainly on the monoaminerg ic neurotransmi tters New mechanisms targeting the monoamines are under development Many novel antidepressa nt targets are in development , including the neurokinins , glutamate, purinoceptors , opioids and trophic factors Novel therapeutic options are likely to emerge
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39. Berk M, Wadee AA, Kuschke RH, O’Neill-Kerr AJ (1997) Acute phase proteins in major depression. J Psychosom Res 43: 529 ± 34. 40. Hellstrand K and Hermodsson S (1987) Role of serotonin in the regulation of natural killer cell activity. J Immunol 139: 869 ± 75. 41. Niiranen A, Laaksonen R, Iivanainen M et al (1988) Behavioral assessment of patients treated with alpha-interferon. Acta Psychiatr Scand 78: 622 ± 6. 42. Lishman WA (1987) Organic Psychiatry: The psychological consequences of cerebral disorder. Blackwell Scientific, Oxford. 43. Grossman CJ (1985) Interactions between the gonadal steroids and the immune system. Science 227: 257 ± 61. 44. Xia Z, DePierre JW, NaÈssberger L (1996) Tricyclic antidepressants inhibit IL-6, IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells. Immunopharmacology 34: 27 ± 37. 45. Shintani F, Nakaki T, Kanba S et al (1995) Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. J Neurosci 15: 1961 ± 70. 46. Connor TJ, Leonard BE (1998) Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci 62: 583 ± 606. 47. Cohen BM, Zubenko GS (1988) Captopril in the treatment of recurrent major depression. J Clin Psychopharmacol 8: 143 ± 4. 48. Martin P, Massol J, Peuch AJ (1990) Captopril as an antidepressant? Effects on the learned helplessness paradigm in rats. Biol Psychiatry 27: 968 ± 74. 49. Murphy BEP, Dhar V, Ghadirian AM et al (1991) Response to steroid suppression in major depression resistant to antidepressant therapy. J Clin Psychopharmacol 11: 121 ± 6. 50. Wolkowitz OM, Reus VI, Manfredi F et al (1993) Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 150: 810 ± 2. 51. Mansbach RS, Brooks EN, Chen YL (1997) Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist. Eur J Pharmacol 323: 21 ± 6. 52. Berk M, Plein H, Belsham B (2000) The specificity of platelet glutamate receptor supersensitivity in psychotic disorders. Life Sci 66: 2427 ± 32. 53. Maj J, Rogoz Z, Skusa G, Sowinska H (1992) Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur Neuropsychopharmacol 2: 37 ± 41. 54. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185: 1 ± 10. 55. Javitt DC, Zukin SR (1991) The role of excitatory amino acids in neuropsychiatric illness. Am J Psychiatry 148: 1301 ± 8. 56. Berk M, Plein H, Ferreira D, Jersky B (2000) Platelet adenosine A2A receptor subsensitivity in major depressive disorder. Presented at the 22 Congress of the Collegium Internationale Neuro-Psychopharmacologicum, Brussels. 57. Williams M (1989) Adenosine: the prototypic neuromodulator. Neurochem Inter 14: 249 ± 64. 58. Williams M (1995) Purinoceptors in central nervous system function. Targets for therapeutic intervention. In Psychopharmacology: The fourth generation of progress (eds FE Bloom, DJ Kupfer) 643 ± 56. Raven Press, New York. 59. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM (1997) Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav 56: 131 ± 7. 60. Altar CA (1999) Neurotrophins and depression. Trends Pharmacol Sci 20: 59 ± 61. 61. Bennett DA Jr, Phun L, Polk JF et al (1998) Neuropharmacology of St. John’s wort (Hypericum). Ann Pharmacother 32: 1201 ± 8.
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62. MuÈller WE, Rolli M, SchaÈfer C, Hafner U (1997) Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 30 (suppl 2): 102 ± 7. 63. Neary JT, Bu Y (1999) Hypericum LI 160 inhibits uptake of serotonin and norepinephrine in astrocytes. Brain Res 816: 358 ± 63. 64. Raffa RB (1998) Screen of receptor and uptake-site activity of hypericin component of St John’s wort reveals Sigma receptor binding. Life Sci 62: 265 ± 70. 65. Linde K, Ramirez G, Mulrow CD et al (1996) St John’s wort for depression ± an overview and meta-analysis of randomised clinical trials. Br Med J 313: 253 ± 8. 66. Linde K, Berner M (1999) Has hypericum found its place in antidepressant treatment? Br Med J 319: 1539. 67. Massot O, Grimaldi B, Bailly JM et al (1998) Magnetic field (MF) affects 5-HT1 B receptor function in brain: Molecular and cellular studies. Eur Neuropsychopharmacol 8 (Suppl 2): S119.
68. Belmaker RH, Grisaru N (1998) Transcranial magnetic stimulation in mania. Eur Neuropsychopharmacol 8 (Suppl 2): S120. 69. SchlaÈpfer T E, Rupp F, Fisch HU, Hess CW (1998) Effect of rTMS and ECT on gene expression: Same or different antidepressant mechanisms? Eur Neuropsychopharmacol 8 (Suppl 2): S121. 70. George MS, Bohning DE, Nahas Z et al (1998) Functional neuroimaging studies of TMS: SPECT, PET and fMRJ. Eur Neuropsychopharmacol 8 (Suppl 2): S122. 71. Pascual-Leone A, Keenan J, Freund S et al (1998) Repetitive transcranial magnetic stimulation trials in depression. Eur Neuropsychopharmacol 8 (Suppl 2): S123. 72. Klein E, Kreinin I, Chistyakov A et al (1999) Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry 56: 315 ± 20.
2000 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2000 Volume 4 Pages 281 ± 286
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Depression therapy: Future prospects MICHAEL BERK
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Department of Psychiatry, University of the Witwatersrand, South Africa Correspondence Address Dr M Berk, Department of Psychiatry, University of the Witwatersrand Medical School, 7 York Road, Parktown, South Africa, 2193 Tel: 27-11-647 2026 E-mail: [email protected]
Received 15 April 1999; Revised 5 April 2000; Accepted 1 June 2000
Current biological approaches to the treatment of depression focus mainly on modification of monoaminer gic neurotransmission. New agents targeting these neurotransmitters are under developmen t. Many novel antidepressan t targets are however under investigation. These include the neurokinins, glutamate , purinoceptors, opioids and trophic factors. While many of these potential targets are likely to fail clinical developmen t, exciting novel therapeutic options are likely to emerge. (Int J Psych Clin Pract 2000; 4: 281 ± 286) Keywords depression glutamate receptors opioids dopamine
INTRODUCTION
T
he discovery of antidepressan t action was initially accidental, as, for example, with iproniazid, an anti-tuberculo us agent found to have antidepressan t activity. Many tricyclics, initially developed as antihistamines, were similarly found to have antidepressan t efficacy. The second phase of development was marked by the identificatio n of the antidepressa nt mechanisms of action, such as MAO inhibition and re-uptake inhibition, and led to the development of specific agents such as fluoxetine . In the third phase, in which we are currently, agents which combine multiple identified monoaminerg ic mechanisms are being developed. Examples of this group include venlafaxine , a serotonin and noradrenalin e (and to a lesser extent, dopamine) re-uptake inhibitor, nefazodone, a 5HT2 antagonist and weak 5HT re-uptake inhibitor, and mirtazapine, an alpha-2 antagonist and 5HT2 and 5HT3 antagonist.1 The promise of higher response rates in this group has not really been fulfilled . The safety issues that limited the first generation of antidepressan ts had been largely solved by the newer agents. Nevertheless , significan t challenges remain. All current agents are still targeting the same monoamine transmitters, albeit through different mechanisms . No agent has broken the 60 ± 70% response rate barrier. Adverse events remain an issue; anticholinerg ic side-effect s have simply been replaced by sexual dysfunction , which has (for example) been replaced by weight gain. Despite much marketing mileage suggesting the contrary, speed of response remains largely unaltered through the generations of drugs (Table 1).2
neurokinins purinoceptors neurotrophins serotonin
An interesting trend, mirroring the development of agents with multiple mechanisms of action, is a return to a more targeted polypharmac y where antidepressan ts with complementary mechanisms of action are combined, particularl y in refractory cases. Of perhaps the greatest interest, however, is the development of agents with entirely novel mechanisms of action, targeting transmitters such as substance P, encephalins and N-methyl-D-as partate (NMDA). It is however likely that very few hypotheses will translate into successfu l agents. Many methodologica l pitfalls exist in the development of novel agents. The screening of new agents uses animal models of depression , such as the forced swimming test. There is a real risk that tests validated using older agents may not be sensitive to novel mechanisms of action.3 A current issue in clinical trials is the very high placebo response rates in many outpatient trials, which has seen the demise of many promising agents. This has led to an increased focus on antidepressa nt trial design and patient selection.4 ,5 Papers for this review were identified by MEDLINE searches using multiple keywords. Due to the massive numbers of citations available, papers of arbitrary clinical interest were selected for review.
FUTURE POSSIBILITIES MONOAMINES Many novel approaches to the development of antidepressant therapies are under development . Novel monoaminergic mechanisms of action, involving for example the 5HT6 and 5HT7 receptors, are under investigation . It is of
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ties.1 9 Pramipexole , a dopamine agonist, shows eficacy in animal models.2 0
Table 1 Antidepressant classification First generation Second generation Third generation
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Fourth generation
Accidentally dirty ± tricyclic agents Deliberately clean ± the selective agents Deliberately dirty ± multiple monoaminergic mechanisms of action Novel mechanisms and neurotransmitters
interest that certain established antidepressan ts, such as clomipramine , amitriptyline , mianseri n and clozapine , have been shown to have activity at the 5HT6 and 5HT7 receptor. 6 ,7 Attempts to combine serotonin re-uptake inhibition (SSRI) with other mechanisms are under development , and include LY 233708, which is an SSRI with 5HT1 A properties, and litoxetine, an SSRI with 5HT3 properties.8 Most drugs exist as a mixture of racemic forms. Chirally different forms often have pharmacodyn amic and pharmacokinetic differences . Chirally pure drugs may differ from mixed forms in ways that may translate into a clinicall y meaningful advantage. Fluoxetine, for example, exists as Rand S-enantiomers . R-fluoxetine may have enhanced activity at 5HT2 A and 5HT2 C receptors compared to Sfluoxetine, and have no active metabolites.9 ,1 0. Similarly, the pharmacologi cal activity of citalopram may lie in its S+ enantiomer.1 1 SSRIs initially cause an attenuated firing of 5HT neurons, due to 5HT1 A somatodendrit ic agonism. As 5HT1 A receptors downregulate , the firing rate again increases, which correlates with the clinical response . The possibilit y that prevention of initial suppressio n could speed up response has been investigated.1 2 Pindolol is a beta-blocker and 5HT1 A antagonist. There is some evidence of enhanced speed of action when pindolol is used together with SSRIs, and possibly greater response ratest. The data however are currently equivocal , with encouraging openlabel studies not being fully supported by controlled data. 1 3 ± 1 5 Dopamine is a neglected monoamine, and many agents with dopaminergi c properties are definitely efficacious in depression . The MAO inhibitors amphetamin e and nomifensine are effective antidepressa nt agents with prominent dopaminergi c properties. There is concern regarding the risks of dependance, particularl y with dopamine-rel easing agents, and of the potential of all dopaminergi c agents for aggravatio n of psychosis . Amineptine and medifoxami ne are dopamine re-uptake inhibitors that have potential antidepressan t efficacy.7 ,1 6 Lisuride is a dopamine and serotonin agonist under development which has affinity for 5HT6 and 5HT7 receptors. 1 7 Dopamine antagonists such as sulpiride 1 8 and olanzapine may have antidepressan t proper-
SUBSTANCE P Substance P (SP), also known as neurokinin-1 , is the most widespread neurokinin in the central nervous system. It is found particularly in brain areas, mediating stress and affective response . In addition, noradrenalin e- and 5HTcontaining neurons often co-express SP. Conventional antidepressa nts are known to downregulat e SP synthesis. Substance P antagonists are under development , and preclinica l assays of antidepressa nt activity have shown the SP antagonist MK 869 to be positive. A phase-2 randomized placebo- controlled double-blin d trial was positive, but a subsequent trial reported negative results. There appears to be a dose-respons e relationship with SP antagonists. More potent SP antagonists are in development. 2 1 ,22
OPIOIDS; MELATONIN The opioids include the encephalins , dynorphins and endorphins . They have long been known to modulate mood. The opioidergi c system may be involved in the antinociceptive effects of the antidepressa nts.2 3 Preclinical studies of an encephalinas e inhibitor, BL-2401, show anti-nocicept ive and antidepressan t effects.2 4 RB 101, an inhibitor of encephali n catabolism, also has antidepressa nt effects in preclinica l models.2 5 Melatonin is a neurohormon e, whose major known role is in circadian rhythms. Depression is a documented sideeffect of melatonin. A melatonin agonist, S20304, demonstrates evidence of antidepressa nt efficacy with chronic administratio n in animal models.2 6 Preliminar y open-label studies present conflicting evidence on the use of melatonin in depression .2 7 ,28 A role in seasonal patterns of depressio n is provisionall y suggested. It is possible that the effect of melatonin on mood may be mediated via 5HT2 a receptors. 2 9
SECOND MESSENGERS, NITRIC OXIDE Most antidepressa nts indirectly affect second messengers , and lithium has direct effects on second messenger systems. Chronic administratio n of antidepressan ts upregulates the cyclic adenosine monophospha te pathway at many levels, including increased expression of the cAMP response-ele ment-binding protein (CREB).3 0 Forskoli n and NKH477 are agents that elevate the cyclic AMP cascade, and both show in vivo antidepressan t efficacy.3 1 Rolipram is a phosphodiest erase inhibitor that increases cAMP. Initial positive trials were however followed by disappointin g results. 3 2 Nitric oxide (NO) is a free gas that is synthesized from arginine by NO synthase and diffuse s into adjacent cells, where it binds to many targets including activating guanyl
Depression therapy: Future prospects
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cyclase and increasing cyclic guanosine monophospha te. Carbon monoxide may also be a neurotransmi tter with NMDA effects. Nitric oxide interacts with glutamate (NMDA), opioid and glucocorticoi d pathways. There is some evidence that antidepressan t anti-nocicepti ve activity may be mediated by nitric oxide.3 3 Methylene blue inhibits nitric oxide synthase and has antidepressan t and antianxiety effects in animal models.3 4 Nitric oxide has a role in sexual function, particularl y in smooth muscle relaxation.3 5 Sildenafil , which potentiates nitric-oxide- mediated smooth muscle relaxation,3 6 may have a role in antidepressa ntinduced sexual dysfunction .3 7 ,38
CYTOKINES There is increasing evidence that depression may be an inflammatory disease. Depression has long been associated with impaired immune function. Recently, immunologic al activation has been recognized, with increased levels of cytokines such as interleukins , complement and interferon reported in some studies.3 9 Neurotransmi tters such as serotonin and the immune system interact with each other. Serotonin modulates lymphocyte proliferatio n and natural killer cell activity. Anti-serotonin and anti-serotonin receptor antibodies have been found in depressiontc . In addition, cytokines are reported to raise NA and 5HT turnover. 4 0 Healthy patients given cytokines develop depressive symptoms.4 1 Depression is far more common in autoimmune and inflammator y diseases such as multiple sclerosis and systemic lupus erythematosis than in the general population.4 2 Women, who have higher rates of mood disorder, have higher cytokine levels, especially during the postpartum period, the highest risk period for the development of mood disorder.4 3 There is some evidence that stress-induc ed cytokine secretion may cause depressive symptoms. Established antidepressa nts such as clomipramine , citalopram and imipramine inhibit cytokine release. 4 4 Interleukin- 1 receptor antagonists prevent the development of learned helplessnes s in rats.4 5 ,4 6
ANGIOTENSIN, GLUCOCORTICOIDS Many cardiac drugs are capable of aggravating mood symptoms. Angiotensin may be involved in mood regulation. The angiotensin-c onverting enzyme inhibitor captopril is reported to show antidepressa nt properties. The drug is positive in animal screening tests. Comparative trials against enalapril show that captopril has an advantage in quality of life, a measure containing many mood variables. However, no formal clinical trials in depression have been done. Captopril may nevertheless be seen as a first-line antihypertens ive in depressed patients.4 7 ,48 Glucocorticoi ds are one of the oldest hormones that have been documented as being altered in depression . Elevated adrenocortico trophic hormone (ACTH) and cortisol activity, as well as Dexamethaso ne suppressio n test non-suppres sion, have long been shown in depression .
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In open trials for resistant depression , glucocorticoi d antagonists, including ketoconazole , amino glutethamide, and metapyrone, have been reported to be efficacious .4 9 Ketoconazole has been found to be of value in depressed patients with raised cortisol levels;5 0 controlled data is however lacking. A corticotrophin-releasing factor (CRF) antagonist, CP-154,526, has been shown to be positive in animal models of depression .5 1
GLUTAMATE Glutamate receptors, particularly the NMDA subtype, may have a role in depression . Supersensiti ve platelet NMDA receptors are found in depression with psychotic features,5 2 as well as in non-psychot ic depression (Berk et al, unpublished ). Imipramine has been shown to have NMDA effects. The NMDA antagonist MK 801 has been shown to be positive in animal models, although tolerability issues preclude its use in clinical practice.5 3 ,5 4 It is well established that NMDA antagonists such as phencyclidi ne can cause psychosis. 5 5
PURINOCEPTORS Purinoceptor s, particularly the adenosine receptor, have been examined in depression . Adenosine is a prototypic neuromodula tor. Theophyllin e and caffeine are antagonists at purinoceptor P1 receptors, and can cause anxiety. Tricyclic antidepressan ts are known to inhibit adenosine re-uptake and potentiate actions of adenosine. Blunted adenosine platelet A2a receptor function is reported in depression.5 6 Electroconvul sive therapy upregulates A1 (a subclass of the P1 receptor). Adenosine A1 and A2a antagonists showed antidepressa nt effects in animal models but were withdrawn from clinical trials.5 7 ,58
NEUROTROPHINS The neurotrophins are another novel antidepressa nt target. Brain-derive d neurotrophic factor (BDNF) promotes function, sprouting and regrowth of neurons. Infusions of BDNF show antidepressan t effects in animal models.5 9 Stress has been shown to decrease BDNF, and certain antidepressa nts may increase BDNF. Neurotrophin stimulants may be promising antidepressan t targets6 0
HYPERICUM Herbal remedies such as Hypericum (St John’s wort) have gained widespread popular acceptance, with modest evidence of efficacy and minimal safety data. Hypericum appears to contain many active compounds. The mechanism of action of hypericum is unclear, with reported pharmacolog ical properties including monoaminer gic reuptake inhibition , GABA agonism, MAO blockade, sigma affinity, and muscarinic anticholiner gic affinity.6 1 ± 6 4 There is some evidence that hypericum is superior to placebo and
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as effective as standard antidepressa nts in mild to moderate depression , although some studies had methodological limitations.6 5 ,6 6 There are some concerns regarding drug interactions with anaesthetic agents and other serotonergi c antidepressan ts. Much additional data is necessary before hypericum is established in terms of efficacy and safety.
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TRANSCRANIAL MAGNETIC STIMULATION Transcrania l Magnetic Stimulation (TMS) is an experimental therapeutic modality. Magnetic fields may alter mood and anxiety. Experimental studies have shown that magnetic stimulation can cause downregulat ion of the 5HT1 B receptor. Like ECT, TMS can activate immediate early genes. Left prefrontal TMS has been shown by positron emission tomography (PET) to increase 1 8 Ffluorodeoxyg lucose uptake. Antidepressa nt effects of left prefrontal TMS at high (20 Hz) frequency, but not of right prefrontal TMS, have been reported. Younger, right-handed patients are more likely to respond. Gabapentin may enhance the therapeutic response to TMS. Right prefrontal TMS may possibly be antimanic.6 7 ± 7 1 Controlled data on the short-term use of TMS in recurrent depression are now available. 7 2
focussed approach to the development of novel therapeutic approaches. It is thus of clinical importance to focus research on markers of physiologica l disturbance outside the monoamines . It is clear that depression involves a far wider net than the monoamines ; however, what is at issue is which of these changes are core changes and which are ripple effects. The currently available supply of drugs for depressio n targets a small number of the systems shown to be involved. In conclusion, many avenues are open for study. These include modification of existing techniques and mechanisms, as well as the development of novel mechanisms and targets. While most of these novel targets are not likely to yield clinically useful results, the development of exciting new therapies is inevitable.
KEY POINTS
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CONCLUSION Advances in the understandi ng of the neurobiologi cal changes in major depressio n should lead to a more
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Current treatment of depression focuses mainly on the monoaminerg ic neurotransmi tters New mechanisms targeting the monoamines are under development Many novel antidepressa nt targets are in development , including the neurokinins , glutamate, purinoceptors , opioids and trophic factors Novel therapeutic options are likely to emerge
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