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Beyond Monoamines Towards the Development of Novel Antidepressants Oltre Le Monoamine Al Fine Di Sviluppare Nuovi Farmaci Antidepressivi

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Beyond Monoamines Towards the Development of Novel Antidepressants Oltre Le Monoamine Al Fine Di Sviluppare Nuovi Farmaci Antidepressivi Original article • Articolo originale Beyond monoamines towards the development of novel antidepressants Oltre le monoamine al fine di sviluppare nuovi farmaci antidepressivi M. Fornaro1,2 1 Department of “Scienze della Formazione”, University of Catania, Italy; 2 Department of Psychiatry, Veteran Affairs (VA) Hospital, University of California (UCSD), La Hoya, San Diego, CA, USA Summary ated giving priority to RCTs and meta-analyses. At present, the pharmacological management of depression appears is Objective characterized by a wide variety of different augmentation or Herein, a concise review is presented on the current and most switching approaches (Fig. 1). Nonetheless, response rates promising antidepressant pharmacological agents for manage- remain substantially unsatisfactory, thus prompting for the ment of depression. development of novel agents with different mechanisms of action. Materials and methods A PubMed search (1966 - February 2012) was performed using Conclusions the following keywords or their combination: “depression”; Shifting the interest for novel antidepressant drugs beyond the “major depressive disorder”: “antidepressants”; “novel antide- monoaminergic modulation represents (Tables I-III) an intriguing pressant targets”; “monoamine”; “novel antidepressants”. Ad- opportunity to enhance response rates of depression, although ditional literature sources, including most authoritative and up- other issues, including revision of current nosological bounda- dated edited books or pamphlets were examined accordingly. ries, should also be considered. Results Key words All relevant literature sources written in English were evalu- Monoamines • Antidepressant drugs • Novel targets Introduction high priority of pharmaceutical companies 7. The situation changed in 1988, when the introduction of fluoxetine, a Depression is one of the most prevalent psychiatric selective serotonin reuptake inhibitor (SSRI) approved for disorders, and has unfavourable prognosis with con- the treatment of major depressive disorder (MDD) 8, alter- siderable suicide risk 1. Its lifetime prevalence rate in natively generically labelled as “depression”, marked the the United States is estimated to be 16.6%, affecting beginning of a “golden era” of the pharmacological treat- over 30 million people, with more than 80% of these ment of the disorder 9. In fact, although not as effective as individuals experiencing recurrent episodes 2 3. None- theless, despite the clinical and social relevance of the the previously introduced tricyclic antidepressants (TCAs) 10 11 phenomenon, depression still faces considerable unsat- and monoamine oxidase inhibitors (MAO-Is) , the SS- isfactory response rates, thus soliciting the exploration RIs and the latter introduced classes of antidepressants, of novel therapeutic targets to develop more effective still ensured substantial remission rates compared to pla- interventions. cebo while providing a better tolerability profile (although Concerning the pharmacological treatment of depres- not completely devoid of side-effects), thus contributing sion, currently the cornerstone of clinical management, to the widespread pharmacological management of de- numerous agents from different classes have been pro- pression 12 13. Nonetheless, the need for higher response posed since the 1950s, when the mood-enhancing prop- rates for the antidepressant treatment solicited the intro- erties of two anti-tuberculosis agents, isoniazid and ip- duction of novel compounds as well the implementation roniazid 4 5 and imipramine, also a tricyclic compound 6 of enhanced augmentation or switching strategies for cur- were serendipitously observed. Unfortunately, at that time rently available drugs. the number of people diagnosed with “depression” who In this review, the prominent pharmacological opportu- would benefit from these “new” agents was very low, nities for the treatment of depression are briefly outlined, so that the development of antidepressants was not the focusing on novel non-monoaminergic compounds. Correspondence Michele Fornaro, via Teatro Greco 84, 95100 Catania, Italy • Tel. +39 347 4140003 • Fax +39 010 3537681 • E-mail: [email protected] 226 Journal of Psychopathology 2012;18:226-233 Beyond monoamines towards the development of novel antidepressants Materials and methods As a major implication, this possibility has suggested that other antidepressant targets should be explored. Considered sources included all PubMed results written in English (updated to February 2012) systematically re- trieved using the following keywords or their combina- The need for novel antidepressant drugs: tion: “depression”; “major depressive disorder”: “antide- the increasingly crowded antidepressant pressants”; “novel antidepressant targets”; “monoamine”; scenario “novel antidepressants”. Additional literature sources, in- Both pharmacological and clinical considerations con- cluding most authoritative and updated edited books or cerning the efficacy, safety, tolerability and costs influ- pamphlets were evaluated accordingly. ence compliance and outcome of the depressed patient, soliciting novel antidepressant interventions. Results The need for an anticipated onset of action Two hundred and eighty nine randomized clinical tri- als (RCTs) or meta-analyses were assessed, while non- A lag phase of at least 3-4 weeks prior to the onset of an controlled studies were used only when controlled data antidepressant effect is commonly seen with current anti- 27 unavailable. Finally, studies performed in humans were depressant drugs , in contrast with an almost immediate prioritized, while pre-clinical or animal investigations increase in monoamine extracellular levels evident just have been cited only in the absence of corresponding few hours initiation of therapy. evidence in human samples. At least two types of 5-HT auto-receptors are present on the serotonergic neuron. Activation of 5-HT1A recep- tors, present in the somatodendritic area, reduces neu- The monoamine hypothesis of depression ronal firing, resulting in less serotonin release from the and beyond axon terminal. On the other hand, activation of 5-HT1B Since its first conceptualization, 14-16 the “monoamine receptors causes direct inhibition of serotonin release. hypothesis of depression” largely influenced the devel- 5-HT1A is also related to control of serotonergic release opment of novel antidepressant drugs and prescribing through a large feedback loop from terminal to the cell 28 attitudes of clinicians toward MDD 17. This hypothesis body region . It is likely that these auto-restraining proc- essentially focuses on increasing the levels and syn- esses counteract the initial effect of SSRIs as well as other aptic effects of three monoamines, namely dopamine classes of antidepressant drugs that primarily act by sero- (DA), norepinephrine (NE) and the indole amine 5-hy- tonergic modulation, and chronic administration of these droxytryptamine (5-HT) or serotonin, to induce an anti- agents is reported to desensitize both presynaptic and 29 depressant response 18-20. Within the past decades, this postsynaptic 5-HT1A receptors . hypothesis has undergone extensive revision, leading to Similarly, complex pre- and post-synaptic modulations the observation that such synaptic modifications would concern norepinephrinergic modulation. The alpha-2 be due to blockade of monoamine transporters, includ- norepinephrinergic auto-receptors, located both on ax- ing the dopamine transporter (DAT), the norepinephrine on terminals and cell bodies, establish an effective self- transporter (NET) and the serotonin transporter (SERT) 19. regulation system similar to that in serotonergic neurons, However, monoamine levels can increase rapidly fol- which is also believed to become supersensitive during 30 lowing blockade of these transporters, much earlier than depression , while the beta-adrenoceptors are located onset of clinical action, if ever 21 22. The “neurotransmit- post-synaptically. Up-regulation of these receptors has ter receptor sensitivity hypothesis” of depression can been observed in the course of depression, whereas explain this lag phase 23, and is also in agreement with down-regulation of these latter has been related to anti- 31 the neurotransmitter receptor hypothesis focusing on the depressant activity . Nonetheless, despite the discovery abnormal up-regulation of receptors during the course of of the mechanisms held to be responsible, overcoming depression 24. Nonetheless, it is likely that modifications the lag phase of antidepressant drugs remains an unad- in receptor number and/or sensitivity following antide- dressed need 32. pressant treatment require alterations in gene expression, transcription, translation and production of various neu- The need for more effective antidepressants: rotrophic factors as the brain derived neurotrophic factor beyond the SSRIs (BDNF) 25 26. Thus, in addition to modulating monoam- The SSRIs are still the most commonly prescribed antide- ine and receptor levels, the final common pathway of all pressant drugs 13. Nonetheless, their efficacy has highly antidepressants should involve the regulation of various debated, especially for most severe cases of depression 33, trophic factors, rather than just the monoamine balance. which have favoured the use of serotonin norepinephrine 227 M. Fornaro FIGURE 1. Switching and augmentation of strategies are part of routine psychopharmacological practice of the treatment of depression, especially
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