The pharmacodynamic properties of lurasidone and their role in its antidepressant efficacy in bipolar disorder

Abstract

The treatment of bipolar depression is one of the most challenging issues in contemporary psychiatry. Currently only quetiapine, the olanzapine–fluoxetine combination and recently lurasidone are officially FDA-approved against this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of lurasidone fit to a previously developed model which was the first to be derived on the basis of the strict combination of clinical and preclinical data with no input from theory or opinion. The authors performed a complete and systematic review of the literature to identify the pharmacodynamic properties of lurasidone. The original model suggests that a constellation of effects on different receptors are necessary but the serotonin reuptake inhibition does not seem to play a significant role for bipolar depression. On the contrary norepinephrine activity seems to be very important. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition is essential in order to sustain it. Overall the properties of lurasidone fit well the model and add to its validity. A point that needs clarification is norepinephrine reuptake inhibition which is not yet studied for lurasidone.

Introduction

Bipolar depression is the phase bipolar disorder (BD) which is the most refractory to treatment and responsible for most of observed global disability in BD patients (Calabrese et al., 2004, Judd and Akiskal, 2003, Judd et al., 1998, Judd et al., 2002, Post, 2005). However, in spite of this fact, only recently its treatment has become a major focus of research, and still is far behind the manic phase as a research priority. This is partially because until recently our knowledge concerning BD was essentially limited and the efficacy of the so-called ‘mood stabilizing agents’ was overvalued. Unfortunately, in this frame, bipolar depression was erroneously believed either to respond to the traditional ‘mood stabilizers’ or it was considered to be similar to unipolar depression and thus it was treated accordingly. The above are reflected in most treatment guidelines (Fountoulakis et al., 2005, Fountoulakis et al., 2007a, Fountoulakis et al., 2007b, Fountoulakis and Vieta, 2008). Therefore, it is of prime importance that recently, lurasidone was the third agent after quetiapine and the olanzapine–fluoxetine combination which received official approval by the Food and Drug Administration (FDA) for the treatment of bipolar depression.

It is unfortunate that the neurobiology of bipolar depression still remains elusive, and this deprives pharmacologic research from a driving theory to rely on and develop new treatment options. While for unipolar depression there is a strong hypothesis which is based mainly on treatment data (TCAs and SSRIs), and involves primarily the serotonergic system in the brain, this hypothesis is problematic concerning bipolar depression since antidepressants are generally proven ineffective against bipolar depression. A detailed discussion on the role of antidepressants in the treatment of bipolar depression can be found elsewhere (Pacchiarotti et al., 2013).

There have been some efforts till now to develop a neurobiological theory concerning bipolar depression and its treatment. In the first, Yatham et al. (2005) proposed the 5HT-1A receptor as the most likely target. In another one Brugue and Vieta (2007) suggested there is an involvement of dopaminergic activity also. On the basis of quetiapine data alone, Jensen et al. (2008) proposed that norepinephrine reuptake and 5HT-1A receptors mediate the antidepressant effect of quetiapine. However at that time there was not enough scientific knowledge to arrive at a reliable conclusion. The available data today do not support such an assumption, since that the receptor is activated by a number of compounds which were proven not to be efficacious in the treatment of bipolar depression. These include aripiprazole, lamotrigine, ziprasidone and others.

The second theory is the only evidence-based model until today and was proposed by Fountoulakis et al. (2012b). According to this model (which will be described in detail in the discussion section) norepinephrine reuptake and 5HT-1A agonism are central and closer to the core deficit in bipolar depression. This is in accord with both a norepinephrine and serotonin hypoactivity. A second line of neurotransmitter regulation includes 5HT-2A blockade (which further increases serotonin activity). The presence of anticholinergic activity might shift the balance between norepinephrine and acetylcholine further in favor of norepinephrine without the need for an excessive increase in norepinephrine function. If such an excessive increase happens, the risk for switching to mania/hypomania increases. D2 and D3 blockade acts possibly as an antidepressant mechanism. D3 blockade increases dopaminergic activity while D2 blocade has variable effects depending on whether the receptor is pre-or post-synaptic. At a third level, alpha-1 blockade further increases norepinephrine function when necessary, and D1 blockade decreases dopamine function and thus exerts an antimanic action. At the same level regulation of histaminergic activity might play an antimanic role possibly via sedation. A graphic representation of the model is shown in Figure 1.

The complete pharmacodynamic properties of the various agents which contributed in the development of the model are shown in Table 1, as these were identified in the original paper which concerned the development of the model (Fountoulakis et al., 2012b).

Chemically, lurasidone or (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl} hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride is structurally related to perospirone and ziprasidone, risperidone, paliperidone, and iloperidone (Caccia et al., 2012).

The aim of the current article was to systematically search and analyze whether the efficacy of lurasidone against bipolar depression is compatible with the neurobiological model we had proposed and whether it adds to our current neurobiological understanding of BD. This paper will compare the pharmacodynamic profile of lurasidone in relationship to the pharmacodynamic properties of agents with definitely positive and negative treatment data, as well as against the neurobiological model previously proposed. The hypothesis is that lurasidone should act as 5HT-1A agonist, norepinephrine reuptake blocker and antagonist at alpha1 noradrenergic, 5-HT2A, and D1, D2 and D3 as well as muscarinic and H1 histamine receptors.