Current Developments in Psychopharmacology for the Treatment of Depression and Schizophrenia


receptors and antagonism at D3 receptors, showed some promising advantages (e.g. bifeprunox treatment was associated with weight


reduction and reduced cholesterol levels), but in the end the pharmaceutical company was not convinced enough by the clinical results to develop this compound further. One of the compounds acting on the glutamatergic system is RO4917838, a glycine transporter inhibitor, which is currently being tested in phase-III trials.


Besides these traditional transmitter systems, other systems are also being focused on, such as the cannabinoid system, the neurokinin system, the glutamatergic system and the muscarinergic system, the latter only for the treatment of cognitive deficits.6


Finally, besides


the transmitter systems, the immunological system and possibly related therapeutic interventions are increasingly of interest.7


The vast majority of compounds in the pipeline are based on the signal transduction hypothesis, which postulates that basic alterations in receptor-mediated signal transduction induces schizophrenia-like psychopathology. Therefore, normalising the altered signalling with medications targeting receptor and post-receptor molecules should be efficacious in treating schizophrenia. Targeting these transmitter sites has so far been the predominant focus of psychopharmacological research, and the strategy has led to significant advances in our understanding of the pathophysiology of schizophrenia and brain function as a whole. It has been suggested, however, that future strategies should move beyond the current strategies of solely targeting the synaptic neurotransmission at the receptor level to the development of agents that can affect more diverse cellular functions, including intercellular signalling pathways, and the mechanisms involved in synaptic plasticity.8


The molecular genetic hypothesis suggests that relevant effects of susceptibility genes underlie the pathophysiology of schizophrenia, and that targeting drugs at these genes or their associated anatomical and functional pathways might yield novel and more effective treatments for schizophrenia.9,10


Most of the susceptibility genes of schizophrenia, which were found in recent years, appeared to be related to the control of synaptic plasticity and glutamate transmission (particularly N-methyl- D-aspartate [NMDA] receptor function). These findings in genetic studies of schizophrenia might pave the way for hypothesis-driven approaches to develop disease-modifying drugs for schizophrenia. However, so far the genetic approach does not at all fulfil the expectations in the directions of drug development and pharmacogenetic prediction. This reflects the complexity of the field. Schizophrenia is a multi-genetic disorder and those genes predisposing individuals to develop this disease have relatively modest odds ratios and very low explained variance. Most of the genes identified are poorly understood, and most of the risk genes described have implications in the neurodevelopmental pathways and might point towards a new type of intervention with a different focus compared to the classical antipsychotics.


Nevertheless, hope remains that the identification of genetic mechanisms underlying schizophrenia will reveal new targets for drug development.11


The hope extends to the identification of genetic factors that will guide treatment choice in a way that will maximise the chance of efficacy, while minimising the risk of specific side effects.12,13


The Future of Antidepressants


Regarding antidepressants, the current understanding is that antidepressants intervene in the multifactorial aetiopathogenesis


EUROPEAN PSYCHIATRIC REVIEW


predominantly by increasing serotonin, noradrenaline and dopamine due to different mechanisms, predominantly reuptake inhibition. As a consequence, primarily the concentration of these transmitters in the synaptic cleft is increased due to reuptake inhibition or other pharmacological mechanisms.14–16


This induces a complex cascade of


secondary and tertiary mechanisms and finally leads to a new homoeostasis on a more functional level.14


The efficacy of the traditional


antidepressants (mostly tricyclics) and modern antidepressants (mostly selective serotonin reuptake inhibitors [SSRIs] and selective serotonin and noradrenaline reuptake inhibitors [SSNRIs]) is well proven. However, the effect size has been criticised as being too small regarding clinical relevance.17 of all data.18,19


This criticism can be rejected based on a careful analysis


It has been suggested that a disorganisation of circadian rhythms plays an important role in the pathophysiology of major depression, and complaints regarding disturbed sleep are frequent in depressed people. Since endogenous melatonin secretion underlies the regulation of circadian rhythms and sleep, compounds with activity at melatonergic receptors have been proposed as potential novel therapeutics.


Agomelatine, an antidepressant with agonistic properties at MT1 and MT2 receptors and antagonistic properties at the 5-HT2C receptor, has been shown pre-clinically to exhibit robust antidepressive effects in several experimental paradigms.20–22


Clinical trials have demonstrated


the superior efficacy of agomelatine in comparison with placebo, and an at least similar efficacy in comparison with active comparators for the treatment of major depression. Of special clinical interest are its sleep regulation properties.


The delayed onset of action of SSRIs, SSNRIs and other antidepressants is thought to reflect, among other things, the time required for desensitisation of the receptors regulating monoamine release (e.g.


involving several approaches. All these pharmacological strategies seem theoretically meaningful. However, so far, many of them are lacking the evidence for efficacy and superior efficacy in depressive people, and some have not even been tested in people. A compound which should be mentioned here is vilazodone, a 5-HT reuptake inhibitor with a 5-HT1A agonism.24


Relatively advanced is the clinical development of LU AA 21004, which can be pharmacologically characterised as a


5-HT1A agonist, 5-HT1B partial agonist, 5-HT3 antagonist, 5-HT7 antagonist and 5-HT reuptake inhibitor.


Besides the traditional transmitter systems for depression, the glutamatergic systems are becoming increasingly of interest. Extracellular glutamate concentrations are enhanced by various stressors, and an involvement of the NMDA receptor has become apparent in the modulation of stress-induced glutamate responses. Furthermore, chronic antidepressant administration can influence NMDA receptor function and receptor binding profiles, as well as generate regional alterations in messenger RNA (mRNA) expression that encodes multiple NMDA receptor subunits. Non-competitive NMDA antagonists (e.g., MK-801, memantine, ketamine), that reduce glutamatergic transmission at the NMDA receptor, have demonstrated antidepressant-like effects in animal models. In clinical trials, Berman et al.25


reported the first placebo-controlled, double-blind study 19


5-HT1A, 5-HT2C, and α-2 adrenergic receptors). To potentially accelerate the onset of antidepressant action – as well as limit unwanted side effects – current drug development strategies are focusing on designing new antidepressants with dual and/or triple modes of reuptake inhibition and/or with directly targeting the above-mentioned receptors,23


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