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- Conclusions and perspectives
- Conflict of interest
Behavioural and psychological symptoms of dementia (BPSD) constitute a substantial medical challenge among elderly patients. Indeed, the progressive worsening of symptoms including hallucinations, delusions and mood deficits is the major reason for patient institutionalization, and decreased quality of life of both patients and caregivers (Liperoti et al., 2008). Overall, 25–50% of patients with dementia show symptoms of psychosis (Jeste et al., 2008) and 40–60% experience significant depressive symptoms at some stage of the disease (Hersch and Falzgraf, 2007).
BPSD are usually treated with psychotropic drugs, often second-generation antipsychotics (SGA) that produce less extrapyramidal symptoms (EPS) and have better efficacy against negative symptoms than classical ones (Liperoti et al., 2008). However, a recent meta-analysis based on 14 placebo-controlled trials of elderly patients with BPSD revealed only modest effects for three SGA, that is, risperidone, aripiprazole and olanzapine (Maher et al., 2011). In addition, antipsychotics may produce adverse effects including EPS, and cardiovascular and metabolic side effects (Nobili et al., 2009; Schulze et al., 2013). Moreover, antipsychotic drugs may worsen cognitive functioning, which can be a substantial drawback in the case of elderly patients who already suffer from cognitive deficits (Jeste et al., 2008; Vigen et al., 2011).
It should be noted that psychosis in dementia may have a different neurobiological substrate from that in schizophrenia. Indeed, psychotic Alzheimer patients often experience visual hallucinations and misidentifications of caregivers – symptoms that are not commonly found in schizophrenia patients. Conversely, bizarre or complex delusions that occur frequently in patients with schizophrenia are not often observed in dementia patients (Jeste and Finkel, 2000). The distinct nature of psychotic symptoms in dementia suggests that different neurobiological mechanisms are at play. In particular, serotonergic systems may be involved because hallucinations in dementia are similar to those caused by serotonergic agonists such as mescaline or lysergic acid (Marsh, 1979). Strong visual hallucinations can be also evoked by NMDA receptor antagonists such as ketamine or phencyclidine (Siegel, 1978) but are less frequently evoked by dopaminomimetics such as amphetamine or cocaine, which are widely used in preclinical screening of new drugs for schizophrenia (Jones et al., 2011). Currently available antipsychotics were selected primarily for their capacity to oppose the effects of dopaminomimetics, and, therefore, may potentially provide suboptimal therapeutic efficacy in the treatment of BPSD. In particular, they were not selected to provide alleviation of mood deficits or to avoid accentuating cognitive deficits in elderly patients. It may be surmised that novel drugs should be identified which are specifically optimized for treatment of BPSD.
There are substantial data supporting the importance of the serotonin system in the development of BPSD. For example, serotonin receptor gene polymorphisms are associated with visual and auditory hallucinations in patients with Alzheimer's disease (AD) (Holmes et al., 1998). A genetic polymorphism of the serotonin transporter promoter region (L/L genotype) has been associated with aggressive behaviour (Sukonick et al., 2001). Other studies show involvement of 5HT2A and 5HT6 receptors in the pathogenesis of AD (Lorke et al., 2006) as well as association of 5-HT6 receptors with psychotic symptoms in patients with AD (Marcos et al., 2008; receptor nomenclature follows Alexander et al., 2013). 5-HT6 receptor antagonists are also active in a range of models of cognition relevant to psychotic disorders (Loiseau et al., 2008; Rodefer et al., 2008; Arnt and Olsen, 2011) as well as in tests of antidepressant-like and anxiolytic activity (Wesołowska, 2007; Carr et al., 2011). Accordingly, a selective 5-HT6 antagonist, LuAE58054, improved cognitive performance of AD patients, in combination with the acetylcholinesterase inhibitor, donepezil (H. Lundbeck A/S, 2012). Finally, some authors proposed that an improved antipsychotic profile may be achieved by combining 5-HT6 antagonism with an absence of anti-muscarinic activity, as is observed for sertindole, but not clozapine or olanzapine (Rodefer et al., 2008). The possibility of clinical evaluation of sertindole, also with respect to BPSD, was however significantly hampered by its arrhythmogenic potential caused by potent hERG channel inhibition.
Based on the above considerations, we designed a series of novel arylsulfonamide derivatives displaying high affinity for 5-HT6, 5-HT7 and 5-HT2A receptor subtypes, as well as dopamine D2 receptors, and devoid of significant interaction with muscarinic receptors or hERG channels (Kołaczkowski et al., 2012). The compounds were screened in vitro and in vivo as potential treatments for BPSD. As no animal model of BPSD is currently available, studies included measures of antipsychotic-like efficacy [MK-801-induced locomotion and conditioned avoidance response (CAR)], antidepressant-like efficacy [forced swimming test (FST)] and cognitive interference [passive avoidance (PA) test]. We recently used these tests to compare eight antipsychotics (haloperidol, chloropromazine, clozapine, olanzapine, risperidone, aripiprazole, lurasidone and asenapine) that are commonly used for treatment of BPSD. None of the drugs presented an optimal profile, i.e., activity in models of both antipsychotic-like and antidepressant-like activities, at doses that produce no or minimal detrimental effects on cognitive or motor performance (Kołaczkowski et al., 2013). In the present study, we describe the profile of one of our lead compounds, ADN-1184 (Figure 1), in a series of preclinical models (in vitro ligand binding and receptor antagonism and in vivo tests) and discuss its potential relevance to treatment of BPSD.
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- Conclusions and perspectives
- Conflict of interest
In view of the ageing population of many developed countries, BPSD is an increasingly challenging problem, generating onerous social and economic costs for the care of elderly patients. Although atypical antipsychotics are commonly used to treat BPSD, they have substantial limitations due to their propensity to elicit memory deficits, EPS, adverse cardiovascular events and metabolic dysfunction. It is therefore desirable to identify novel treatments that are capable of controlling both psychosis and depressive symptoms without exacerbating cognitive impairment or inducing motor disruption (Jeste et al., 2008).
The present study suggests that ADN-1184 possesses a preclinical profile of activity that corresponds to these criteria. Unlike commercially available antipsychotics, ADN-1184 was active in a series of tests related to both psychotic symptoms and mood deficits without disrupting motor control or memory performance. This favourable in vivo profile is likely mediated by ADN-1184's potent antagonism of 5-HT6, 5-HT7 and 5-HT2A receptors with more modest antagonism of dopamine D2 and D3 receptors.
ADN-1184 is potently active in models of psychosis
In tests related to antipsychotic properties, ADN-1184 showed activity consistent with marked capacity to control psychosis.
Firstly, ADN-1184 reversed hyperactivity induced by the NMDA receptor antagonist, MK-801 (0.3 mg·kg−1). This test is particularly relevant to dementia patients who suffer from psychoses of glutamatergic origin (see Introduction) which may be controlled by potent antagonism of 5-HT2A receptors (Millan et al., 1999).
The potency of ADN-1184 was similar to that of clozapine, olanzapine and lurasidone, as previously tested in the same conditions (Kołaczkowski et al., 2013). In contrast, ADN-1184 was more efficacious in this test than aripiprazole, which only partially reversed MK-801-induced hyperactivity (Kołaczkowski et al., 2013) and did not ameliorate psychotic symptoms in patients with AD (De Deyn et al., 2005). D2 receptor partial agonists may therefore be less ‘incisive’ in controlling NMDA receptor hypofunction-elicited psychosis, as previously noted in other studies (Bardin et al., 2007).
Secondly, ADN-1184 also abolished stereotypies induced by a higher dose of MK-801 (1.2 mg·kg−1). Under these conditions, head weaving and circling behaviour is observed in a complex pattern (Wu et al., 2005). Antipsychotics such as olanzapine or risperidone are capable of completely inhibiting MK-801-induced behaviours (Bradford et al., 2010). The fact that ADN-1184 achieved full reversal of the stereotypies therefore suggests that it has potent ‘antipsychotic-like’ properties.
Finally, ADN-1184 inhibited CAR, an effect typical of antipsychotics (Wadenberg, 2010), in a dose range similar to that of its effects against MK-801-induced hyperlocomotion (MED 3 mg·kg−1; Figure 2). The CAR response was completely abolished, similar to the effect achieved with haloperidol and asenapine under the same conditions, but unlike lurasidone or aripiprazole that exhibited only partial effects (Kołaczkowski et al., 2013).
Taken together, the present results suggest that ADN-1184 possesses incisive antipsychotic activity that is compatible with control of psychotic symptoms such as those observed in BPSD. In particular, glutamatergic dysfunction has been associated with psychotic symptoms in elderly patients suffering from dementia (Scheuer et al., 1996; Olivares et al., 2012).
ADN-1184 is active in models of mood deficits
ADN-1184 was active in a classic model of antidepressant-like activity (Porsolt et al., 1978), thus combining incisive antipsychotic-like activity (see above) with a favourable profile on a test of mood deficit.
Firstly, at low doses, ADN-1184 significantly decreased immobility duration, a measure of behavioural despair, with higher doses not showing significant effects. Risperidone, aripiprazole and lurasidone also exhibited U-shaped effects at low doses (Kołaczkowski et al., 2013) but ADN-1184 was active at two doses (0.3 and 1.0 mg·kg−1; Figure 3) whereas other antipsychotics were only active at a single dose (Kołaczkowski et al., 2013). Nevertheless, clozapine was a notable exception, showing activity in the FST at two doses, similar to ADN-1184 here. These data suggest that ADN-1184 may have promising activity for alleviation of depressive symptoms.
Secondly, ADN-1184 reduced immobility time in the FST by about 20% compared with that of vehicle-treated subjects. In contrast, other antipsychotics, including clozapine and lurasidone, reduced immobility times by about 10–15% when tested under the same conditions. Insofar as an acute effect in this animal model is predictive of clinical efficacy, this suggests that ADN-1184 may have more pronounced effects on mood deficits. It should be noted that the tricyclic antidepressant, imipramine 10 mg·kg−1, decreased immobility times by about 25%, relative to control values (Kołaczkowski et al., 2013), an effect only slightly greater than that of ADN-1184. Thus, the properties of ADN-1184 observed herein are of the same order of magnitude as those of an established antidepressant.
Thirdly, the active dose range of ADN-1184 in the FST is somewhat lower than in tests of antipsychotic-like activity. A similar pattern was observed for other antipsychotics, although not with clozapine. It may be speculated that, for drugs such as ADN-1184, clinical dosing may be adapted according to the symptoms exhibited by BPSD patients: those with depressive symptoms would only need to receive low doses whereas those exhibiting psychotic episodes would warrant increased dosing.
ADN-1184 does not impair performance in a memory test
In view of the fact that BPSD patients experience the full spectrum of cognitive disturbance found in dementia (Hersch and Falzgraf, 2007), it would be desirable to avoid treating them with drugs that elicit or accentuate cognitive impairment.
ADN-1184 did not impair the PA response across a broad dose range that covers activity in the FST, CAR and MK-801-induced behaviours (Figure 3). This contrasts sharply with the effects of clinically used antipsychotics: under the same conditions, all the drugs elicited dose-dependent disruption in the PA test. In the case of clozapine and olanzapine, the doses that impaired performance were lower than those that inhibited the CAR response or MK-801-induced hyperlocomotion (Kołaczkowski et al., 2013), indicating that antipsychotic-like effects are accompanied by interference with memory function. In contrast, ADN-1184 shows therapeutic-like activity without impairing memory performance, suggesting that it is possible to identify drug candidates that are more compatible with treatment of patients with dementia.
ADN-1184 does not elicit motor interference at ‘therapeutic’ doses
While being active in models of psychosis and mood deficit, ADN-1184 did not elicit catalepsy, except weakly at a high dose (30 mg·kg−1; Figure 4). This differentiates ADN-1184 from other antipsychotics, including risperidone or haloperidol, which are still used in agitated patients (Carson et al., 2006). These drugs elicit dose-dependent EPS (Rummel-Kluge et al., 2012), a side effect that may be especially disruptive in elderly patients who already suffer from motor difficulties.
A related measure of motor impairment is inhibition of spontaneous locomotor activity as determined by the distance travelled by the subject in an open field. Even antipsychotics that do not elicit catalepsy, such as clozapine, may potently decrease locomotor activity because of their sedative properties (Miller, 2000). In fact, decreased locomotor activity was observed for reference drugs over a similar dose range as that which elicits antipsychotic-like activity (Kołaczkowski et al., 2013). In contrast, ADN-1184 only began to decrease locomotor activity at doses (MED 30 mg·kg−1) that were significantly greater than those active in the ‘therapeutic’ tests.
ADN-1184 exhibits a novel profile of receptor interaction
A distinctive in vitro profile may underlie the differentiation of ADN-1184 from current atypical antipsychotics. The latter generally interact with many different receptor targets, including those that may elicit some side effects and/or limit their therapeutic efficacy. For example, these drugs also bind potently to muscarinic and histamine receptors which are associated with cholinergic interference and sedation respectively. In addition, they act as potent 5-HT2C receptor antagonists, a property that is a risk factor for metabolic dysfunction (Reynolds and Kirk, 2010; Bai et al., 2011). Aripiprazole is well tolerated but its partial agonist activity at dopamine D2 receptors may limit its efficacy for control of psychotic symptoms in elderly patients (De Deyn et al., 2005).
In contrast to these drugs, ADN-1184 combines dopamine D2 and D3 receptor antagonism with potent blockade of 5-HT6, 5-HT7 and 5-HT2A receptors in the absence of anticholinergic effects (Tables 1 and 2). This profile may underlie its unusual combination of antipsychotic-like and antidepressant-like activities without cognitive or motor impairment. Indeed, as described in the Introduction, 5-HT6 receptor antagonism is associated with beneficial effects on mood and cognitive parameters (Geldenhuys and Van der Schyf, 2009; Hirano et al., 2009). In the case of ADN-1184, its affinity for 5-HT6 receptors is of the same order of magnitude as that for D2 receptors and likely to be expressed at antipsychotic doses. Nevertheless, it is possible that a different balance of 5-HT6/D2 affinity could yield a pharmacological profile that shows improved activity.
In the case of 5-HT7 receptors, a growing body of work indicates that blockade of these sites mediates antidepressant and pro-cognitive properties (Galici et al., 2008; Hedlund, 2009; Bonaventure et al., 2011). In addition, 5-HT7 receptor antagonism induces antipsychotic-like activity in animal models (Galici et al., 2008) and may underlie some therapeutic properties of lurasidone (Ishibashi et al., 2010). It should also be noted that amisulpride, which shows clinical antidepressant properties in addition to antipsychotic activity, possesses 5-HT7 receptor antagonist activity (Abbas et al., 2009; Ishibashi et al., 2010).
ADN-1184 also interacts with α1 adrenoceptors. Antagonism at these receptors is a prominent feature of the receptor profile of many antipsychotics including clozapine, risperidone and quetiapine (Arnt et al., 2008; Newman-Tancredi and Kleven, 2011) and may contribute to their therapeutic activity. Indeed, in combination with modest dopamine D2 receptor occupancy, α1 adrenoceptor blockade might improve antipsychotic efficacy and widen the therapeutic window with regard to EPS (Wadenberg et al., 2000). In addition, α1 adrenoceptors are highly co-expressed with 5-HT2A receptors in prefrontal cortex (PFC), suggesting that combined blockade of both these targets, as found in ADN-1184, may provide more robust control of PFC function (Santana et al., 2013). Furthermore, in AD patients, (i) deregulation of α1 adrenoceptors has been reported in frontal cortex of post mortem brain (Szot et al., 2006); and (ii) treatment with the α1 adrenoceptor antagonist, prazosin, reduced agitation and aggressive behaviour in a pilot clinical trial (Wang et al., 2009). While these observations suggest that α1 adrenoceptor antagonism may be desirable in drugs targeted at BPSD, antagonism of peripheral α1 adrenoceptors is associated with cardiovascular effects, notably hypotensive activity, which would need to be addressed in elderly patients with potentially fragile cardiac function.
In comparison, ADN-1184 has only moderate or low affinity for other receptor targets, including hERG channels associated with cardiovascular risk (Table 1) or muscarinic and histamine receptors. Antagonism of the latter sites is associated with cognitive interference and sedative properties, respectively, so the low affinity of ADN-1184 at these sites is likely to underlie its freedom from impairment of performance in the PA test and only modest inhibition of spontaneous locomotor activity.
Conclusions and perspectives
- Top of page
- Conclusions and perspectives
- Conflict of interest
The present study shows that ADN-1184 (i) is potently active in tests of antipsychotic-like activity; (ii) exhibits antidepressant-like activity; and (iii) does not disrupt performance in a memory test or in motor coordination. This profile of in vivo activity is promising in the context of identifying novel treatments for BPSD. Indeed, current antipsychotics do not possess such a favourable profile and there is an unmet need for novel pharmacotherapeutic agents that are better suited to elderly patients.
However, the in vivo results described here were all obtained upon acute administration and it is necessary to determine the effects of the compound following repeated administration. Indeed, antidepressant-like effects may become more accentuated upon chronic treatment (Morley-Fletcher et al., 2004), possibly increasing the dose range that is active in the FST. Further, it would be interesting to determine the capacity of ADN-1184 to reverse memory deficits elicited by a muscarinic antagonist such as scopolamine. Indeed, we would expect the pronounced 5-HT6 antagonist properties of ADN-1184 to favour cholinergic transmission and improve memory function in elderly patients (Da Silva Costa-Aze et al., 2012; H. Lundbeck A/S, 2012).
Taken together, the present data indicate that it is possible to identify drug candidates that exhibit an in vivo profile of action that is consistent with potentially improved management of BPSD. Indeed, ADN-1184 is an example of an investigational drug that exhibits activity in animal models of psychosis and mood deficit without disrupting memory or eliciting motor side effects.