The principal finding of the present study is that currently-marketed second-generation antipsychotics offer limited separation between doses active in rat models of antipsychotic-like activity and memory impairment. Although, in accordance with clinical data, their propensity to produce catalepsy was lower, the drugs all elicited pronounced sedation. Indeed, although antipsychotics are commonly used to treat BPSD off-label, little information is available that directly compares antipsychotics in standardized pharmacological tests that may be relevant to this disorder. Thus, whereas previous studies have reported data on antipsychotic-like properties (e.g., inhibition of MK-801-induced hyperlocomotion), comparisons of these activities with those observed in PA and FST have not been thoroughly characterized. Such early-stage comparative information is important to provide a basis on which to select future drug candidates at a preclinical level. Indeed, although BPSD is a serious and unmet medical need, there is currently no consensus for identifying novel drugs with improved therapeutic potential. The present study therefore provides a comparative dataset for novel drug candidates such as the recently reported compound, ADN-1184 (Kołaczkowski et al. 2013).

Activity of compounds in tests of antipsychotic-like efficacy and motor control

Inhibition of MK-801-induced hyperactivity was used here as a measure of antipsychotic-like activity. This test was chosen because NMDA receptors are involved in various forms of dementia (Olivares et al. 2012) and NMDA receptor density is decreased in the frontal cortex of postmortem brain samples of Alzheimer’s disease patients (Scheuer et al. 1996). This suggests that dysfunction of NMDA receptors may underlie some aspects of the disease, such as susceptibility to psychotic symptoms. In the present experiments, most of the antipsychotics abolished MK-801-induced hyperactivity, as expected. Among the recent drugs, lurasidone and asenapine, but not aripiprazole, displayed robust activity in this test. In contrast, other authors have reported significant inhibition by aripiprazole of MK-801 and ketamine-induced hyperactivity in rat and mouse (Leite et al. 2008; Nordquist et al. 2008). One reason for the discrepancy may be the somewhat variable response observed with aripiprazole herein (Fig. 1). However, the D2 receptor partial agonist properties of aripiprazole likely also render it less adapted to antagonizing hyperlocomotion elicited by NMDA receptor antagonists, as suggested by previous studies (Bardin et al. 2007; Leite et al. 2008). Indeed, the present data correlate with the modest efficacy of aripiprazole in controlling psychotic symptoms in Alzheimer’s disease patients (De Deyn et al. 2005; Schneider et al. 2006a), suggesting that reversal of NMDA receptor antagonist-induced hyperactivity is an important selection criterion for future drugs aimed at treatment of BPSD. Overall, the results from the MK-801 test are consistent with antipsychotic-like activity of the drugs and are important in the present study because they identify active doses that constitute measures of central activity for comparison with the other tests relevant to BPSD (see below).

In tests of catalepsy and inhibition of locomotor activity, the drugs displayed expected profiles: Most of the drugs elicited dose-dependent catalepsy, a model of EPS, but clozapine, aripiprazole, and lurasidone did not (Table 1). However, all the drugs tested herein inhibited spontaneous locomotor activity, probably reflecting sedative properties, at doses similar to those active in the MK-801 test (although antipsychotic-induced sedation can progressively attenuate with repeated administration). This is an issue that may be significant in the context of BPSD drug discovery because elderly patients may suffer from poor motor coordination and/or movement disorders (Fasano et al. 2012). Care is necessary when using drugs that are known to induce motor disruption, and it would therefore be desirable to identify new drug candidates that did not suffer from such motor disruption liability.

Activity of compounds in a test of antidepressant-like efficacy

Mood deficits and depressive symptoms are very common in patients suffering from dementia (Hersch and Falzgraf 2007), and the present study shows that antipsychotics used in the treatment of BPSD have distinct effects in the FST, a classic model of antidepressant-like activity (Fig. 2). Firstly, the capacity of antipsychotic drugs to alleviate symptoms of depression is being increasingly recognized with the clinical use of olanzapine, risperidone, and aripiprazole to treat treatment-resistant and bipolar depression in conjunction with established antidepressants (Komossa et al. 2010) or, in the case of quetiapine, as monotherapy (Weisler et al. 2012). Clearly, inhibition of monoamine reuptake by SSRIs, SNRIs, or tricyclic drugs does not provide optimal antidepressant therapy in many patients. Indeed, established antidepressants induce a broad increase in monoamine transmission that affects all serotonergic and noradrenergic receptors, including those that limit antidepressant response, such as, for example, 5-HT6 and 5-HT7. Thus, the efficacy of adjunct treatment with antipsychotics may be due to antagonism of targets that limit antidepressant action (Carr et al. 2011).

Secondly, in most cases, the effects of the drugs herein were observed at only a single dose. This is likely a reflection of the multireceptor profiles of antipsychotics that can, presumably, interfere with the drugs’ capacity to alleviate mood deficits over a broad dose range. Olanzapine and lurasidone were active at doses that are 3-fold lower than those active in the MK-801 test (Table 1). In contrast, risperidone was active in the FST at the same dose that was first active in the MK-801 test. Interestingly, very low doses of haloperidol (10–30-fold lower than antipsychotic-like doses) modestly reduced immobility, probably by antagonism of pre-synaptic D2 receptors and facilitation of dopaminergic neurotransmission in limbic regions (Lucas and Spampinato 2000).

Thirdly, the only drug that showed significant activity at more than one dose, overlapping with antipsychotic activity, was clozapine. This antipsychotic is among the most effective in reducing suicidality, a parameter which is strongly connected to depressed mood (Meltzer 2012). Previous studies of clozapine in the FST have shown that it is also active under other experimental conditions (Chindo et al. 2012) and, in a comparative study in mice, was the only antipsychotic that showed activity in the tail-suspension test (Wesolowska et al. 2011). It therefore seems that clozapine’s mood-modulating effects are clearly measurable in pharmacological models, and this might provide a criterion by which to evaluate novel drugs at an early stage of drug discovery.

Fourthly, the antipsychotics reduced immobility times by about 10–15 % compared with vehicle-treated subjects. In comparison, the tricyclic antidepressant imipramine decreased immobility times by about 25 % at the dose tested. Imipramine’s effect is therefore only about 2-fold greater than that elicited by antipsychotic drugs, suggesting that the latter’s effects on mood modulation may be pharmacologically relevant. Nevertheless, higher doses of imipramine are sometimes reported to elicit larger responses so the antidepressant-like effects observed with the antipsychotics should be interpreted with caution (Kitamura et al. 2008). However, it would be interesting to evaluate the activity of clozapine and other antipsychotics in the FST upon chronic treatment—their efficacy may increase with repeated administration, as is the case for reuptake inhibitors, including imipramine (Koek et al. 1998). In addition, in view of the fact that antipsychotics are often prescribed as adjunct treatment, it would be interesting to test them in combination with clinically used antidepressants.

Activity of compounds in a test of cognition/memory

Cognitive disturbance is a major characteristic of dementia (Hersch and Falzgraf 2007). Hence, it would be desirable to avoid treating patients suffering from BPSD with drugs that elicit or accentuate cognitive impairment. Herein, we used a classic memory test to compare the activity of the antipsychotics. The PA is based on the acquisition, storage, and retention of aversive Pavlovian conditioning involving short- and long-term memory processes. In addition, PA also depends on attention, perception (of painful stimuli and visual discrimination between the compartments), and sensorimotor integration that involves multiple neurotransmitter systems (Myhrer 2003). Therefore, PA acquisition is a composite read-out, and gaining information at an early stage on whether a compound impairs PA is of value in selection of new drug candidates for BPSD.

Firstly, the antipsychotics generally showed impairment of the PA response (Fig. 3; Table 1) although their pattern varied from one drug to another. Thus, risperidone impaired PA performance but did so at doses that were 10-fold greater than those active in the MK-801 test. This suggests that it can achieve antipsychotic-like activity in the absence of memory impairment, although its induction of catalepsy and spontaneous locomotor activity remain sub-optimal. Other antipsychotics, including clozapine, olanzapine, lurasidone, and asenapine, showed little (3-fold) or no MED separation between the PA and MK-801 tests. Accordingly, it would be desirable to identify drug candidates that did not disrupt memory performance in early screening tests. Such drugs could then be further characterized in diverse models of cognition relevant to dementia (see below). Also, chronic studies are warranted to assess if repeated administration affects the separation factor between doses that elicit “antipsychotic” effects and those that alter cognitive capacities.

Secondly, the novel antipsychotic lurasidone also impaired PA performance (MED 10 mg/kp, i.p.). This is notable because lurasidone has been claimed to exhibit a favorable cognitive profile in tests of passive avoidance, the radial arm maze, and the Morris water maze, without impairing basal PA performance (Enomoto et al. 2008; Ishiyama et al. 2007). In addition, lurasidone has been reported to attenuate MK-801-induced cognitive deficits at low doses (1–3 mg/kg p.o.) (Ishiyama et al. 2007), suggesting that it may exhibit dose separation between some of its pro-cognitive and antipsychotic-like properties. It will therefore be interesting to determine the extent to which lurasidone is of utility in dementia patients.

Thirdly, the striking absence of memory impairment by aripiprazole is consistent with its generally benign tolerance profile. The partial agonist properties of aripiprazole at D2 and 5-HT1A receptors are claimed to provide “stabilizing” influence on neurotransmission, and this may underlie the drug’s absence of interference on PA performance (Tamminga and Carlsson 2002). Nevertheless, the incomplete blockade of D2 receptors by aripiprazole (due to its partial agonist activity at these sites) may also render it less incisive for control of psychotic symptoms or agitated states, as reflected in its somewhat lesser capacity to reverse MK-801-induced hyperactivity, as noted above, and its lack of clinical antipsychotic efficacy in a trial of Alzheimer disease patients (De Deyn et al. 2005).

Fourthly, the present study examined the effects of antipsychotics on the PA test in normal rats that were drug-naïve and normally express a high level of performance. Therefore, the present conditions detect impairments of memory performance rather than cognitive enhancement (Marston et al. 2009). Ideally, drugs would be active in MK-801-induced hyperactivity tests while reducing immobility in the FST and being free of interference on (or even improving) PA performance. Such a screening battery could, theoretically, identify promising compounds for subsequent characterization in more advanced tests of anxio-depressive states and cognition. For example, drugs could then be tested for their capacity to reverse memory deficits elicited by muscarinic receptor antagonists such as scopolamine (Gravius et al. 2011) and/or examine their effects in aged animals that suffer from impairment arising from decline in cerebral function or in mice that have been genetically modified to alter beta-amyloid expression and neurologically mimic Alzheimer’s disease (Lithner et al. 2011).

Mechanistic aspects

All of the drugs examined herein share the common property of interacting with dopamine D2 receptors, the primary action responsible for their antipsychotic-like profiles. In contrast, the drugs exhibit markedly diverse profiles of action at serotonergic receptor subtypes. In particular, the interaction of some atypical antipsychotics with 5-HT1A, 5-HT6, and 5-HT7 receptors is likely to underlie their effects on antidepressant-like behavior and cognitive performance (Arnt et al. 2008). Thus, 5-HT1A receptor activation mediates the capacity of aripiprazole to reverse social interaction deficits elicited by PCP (Newman-Tancredi and Kleven 2011) and may also underlie some of clozapine’s and lurasidone’s activity (Horiguchi and Meltzer 2012; Ishibashi et al. 2010). Lurasidone also has pronounced 5-HT7 interaction, a property which has been claimed to contribute to its attenuation of PCP-induced novel object recognition deficits (Horiguchi et al. 2011; Ishibashi et al. 2010).

Lastly, 5-HT6 antagonism is a prominent feature of the receptor profile of clozapine and has been suggested to mediate some of its “atypical” properties (Glatt et al. 1995). Indeed, 5-HT6 receptor antagonists are active in models of cognition relevant to psychotic disorders (Arnt and Olsen 2011; Rodefer et al. 2008) as well as in tests of antidepressant-like and anxiolytic activity (Carr et al. 2011). 5-HT6 receptor antagonism may also be a promising target for therapy of Alzheimer’s disease (Gravius et al. 2011): A selective 5-HT6 antagonist, LuAE58054, improved cognitive performance of Alzheimer disease patients (H. Lundbeck A/S 2012). At a drug discovery level, the novel compound, ADN-1184, possesses a promising profile in rat models (active in the MK-801 and FST tests without catalepsy or impairment of PA) and is characterized by potent antagonism of 5-HT6 and 5-HT7 receptors, suggesting that they mediate some of its therapeutic-like properties (Kołaczkowski et al. 2013).

Conclusions and perspectives

To summarize, all the antipsychotics possess sub-optimal profiles, mostly by eliciting memory-impairment or sedation at antipsychotic-like range of doses—side effects that may be of particular concern for elderly dementia patients with preexisting cognitive deficits and motor difficulties. Improved management of BPSD may be achieved by use of drugs that incisively oppose glutamate-related psychosis but do not elicit cognitive deficits or motor impairment. If such drugs also possessed accentuated antidepressant properties, they could constitute promising therapeutics for treatment of dementia-related disturbances in elderly patients. While further investigation would be desirable to determine the effects of drugs under other treatment conditions (e.g., following repeated administration or in conjunction with antidepressants), the present comparative study provides a reference dataset by which future drugs candidates can be evaluated at an early stage of in vivo testing.

Concerning longer-term perspectives, the regulatory framework for development of new BPSD drugs requires clarification. Indeed, this should be addressed in a multidisciplinary context involving experts from pharmaceutical, medical, and social sciences. A critical point is balancing somatic risks induced by use of antipsychotics and their potential to improve clinical status and quality of life of dementia patients and caregivers. Recently, pimavanserin, a drug targeting psychosis in Parkinson’s disease patients, was granted an expedited path to NDA filing, suggesting that the regulatory environment concerning psychotropic drugs for the elderly may be changing. If so, there may be a rise in much-needed drug discovery and development of novel treatments, offering hope for the patients and families of those suffering from disorders (such as BPSD) that are associated with dementia.