By evaluating preventive antipsychotic and antidepressant drug treatment in an infection-based neurodevelopmental mouse model of schizophrenia-like disorder, the present study provides experimental evidence for both beneficial and detrimental effects of these early pharmacological interventions on adult behavioral functions. In subjects predisposed to adult psychopathology as a result of prenatal immune challenge, preventive treatment with the reference antipsychotic and antidepressant drugs HAL, CLZ, and FLX during periadolescence attenuated the emergence of multiple psychosis-related behavioral and pharmacological abnormalities in adulthood (for a summary, see ). Hence, in the absence of preventive pharmacotherapy, offspring born to PolyI:C-challenged mothers developed multiple adult disturbances known to be implicated in schizophrenia, namely PPI disruption,34
and hypersensitivity to dopaminergic and glutamatergic psychostimulant drugs.29,30,38,39
This indicates that periadolescent pharmacotherapy was effective in halting the pathological progression into a full-blown schizophrenia-related phenotype after infection-mediated neurodevelopmental disturbances. At the same time, our results show that chronic periadolescent pharmacotherapy as such is sufficient to induce adult pathological behavior when initiated in CON subjects that were not primed to develop schizophrenia-related abnormalities (). Indeed, we revealed clear bidirectional effects for some of the long-term consequences of periadolescent pharmacotherapy in CON subjects (ie, offspring born to CON mothers) and subjects with predisposition for adult schizophrenia-related disturbances (ie, offspring born to PolyI:C-treated mothers). One particular example is periadolescent HAL treatment, which completely abolished the development of increased AMPH sensitivity in PolyI:C offspring but as such induced an enhancement of AMPH responsiveness in CON offspring (see ).
Summary of the Identified Beneficial and Detrimental Effects of Preventive Pharmacotherapy During Periadolescence on Adult Behavioral and Pharmacological Functions in Prenatally Immune-Challenged Mice (PolyI:C Offspring) and CON Mice (CON Offspring)
It is important to emphasize that the beneficial effects of periadolescent drug exposure in prenatally immune-challenged animals cannot be simply accounted for by “masking effects” of the preventive pharmacotherapy. For example, we show that periadolescent CLZ treatment blocks the prenatal PolyI:C-induced PPI and LI deficits without concomitantly enhancing PPI and LI in CLZ-treated animals born to CON mothers (see and ). Hence, the periadolescent pharmacotherapy exerted corrective but not additive effects on behavioral and pharmacological functions in adulthood. It is well known that offspring born to gestationally immune-challenged mothers display several neuronal abnormalities during the periadolescent period.24,25
Importantly, these early neuronal abnormalities can exist in the absence of multiple behavioral and pharmacological dysfunctions at this stage of development,21,23,25,27
suggesting that the emergence of a wide spectrum of infection-induced behavioral and pharmacological abnormalities in adult life requires aberrant neuronal development and/or maturation from periadolescence to adulthood. Infection-induced interference with fetal brain development is thus expected to significantly affect subsequent postnatal brain development and/or maturation and to lead to adult deficits that are dependent on periadolescent maturational processes. Therefore, given that the antipsychotic or antidepressant drugs were administered to PolyI:C and CON offspring specifically during the periadolescent (but not adult) stage of life, the efficacy of periadolescent pharmacotherapy to block the emergence of prenatal PolyI:C-induced deficits in adulthood may be readily associated with the drugs’ effects on developmental and maturational processes occurring during periadolescent development. Likewise, the identified long-term detrimental effects of chronic periadolescent pharmacotherapy in offspring born to CON mothers are likely to be accounted for by drug-induced interference with normal periadolescent brain development and/or maturation. Further studies are clearly warranted in order to identify the critical neuronal mechanisms underlying these associations in prenatally immune-challenged animals as well as CON subjects.
Both the beneficial and detrimental long-term effects of the periadolescent pharmacotherapy were critically dependent on the pharmacological specificity of the compound administered as well as on the precise psychopathological trait being evaluated (for a summary, see ). Specifically, periadolescent HAL exposure in PolyI:C offspring was effective for the prevention of 3 of 4 schizophrenia-related abnormalities, namely LI deficiency () and increased sensitivity to acute AMPH () as well as MK-801 () challenge. On the other hand, chronic CLZ treatment successfully blocked the emergence of PPI () and LI () deficits induced by prenatal PolyI:C treatment, while it did not exert any corrective effects against psychostimulant hypersensitivity ( and ). Interestingly, the beneficial effects of periadolescent CLZ treatment on PolyI:C-induced PPI disruption seems to be, at least in part, linked to the drug's effect on enhancing the reactivity to prepulse-alone stimuli (). This is consistent with the recent findings that normalization of sensorimotor gating deficiency in medicated schizophrenic patients may be related to the effects of antipsychotic medication on enhancing prepulse-elicited reactivity.40
Finally, chronic treatment with the SSRI FLX attenuated PPI deficits () and enhanced AMPH reaction () induced by prenatal PolyI:C exposure, which however was ineffective against the disruption of LI () and the enhanced reaction to MK-801 (). In offspring born to CON mothers, periadolescent HAL treatment induced marked PPI impairments () and increased basal and psychostimulant-induced locomotor activity ( and ), whereas chronic FLX administration disrupted LI () and potentiated MK-801 sensitivity () in adult life. In contrast, chronic CLZ treatment during periadolescent development was devoid of any negative behavioral effects examined here in adult CON subjects. At the present stage, we can only speculate about the possible mechanisms underlying these differential brain and behavioral effects of periadolescent treatment with distinct classes of pharmacological compounds. One clear possibility would be that chronic antagonism and/or activation of distinct receptor classes and neurotransmitter systems during periadolescent development may be involved in the distinct long-term effects of the early pharmacological intervention, given that the pharmacology of HAL, CLZ, and FLX can be readily distinguished, at least in part, by their specific neurochemical activities and receptor affinities.41,42
The dissociation of the long-term effects of preventive pharmacotherapy in subjects predisposed to adult schizophrenia-related pathology and CON subjects highlights some of the major difficulties and concerns associated with the recent attempts in humans to prevent the onset or to attenuate the severity of psychosis by early pharmacological interventions during the prodromal stage. First, the relatively low conversion rates from the initial prodromal stage to the eventual psychotic phase12,14,15
implies the exposure of a substantial number of false-positive individuals to unnecessary and possibly harmful drug treatment. Reports about long-term detrimental effects of early pharmacological intervention on subsequent brain and behavioral development in false-positive subjects are still lacking because attempts to prevent psychotic behavior by drugs is a relatively recent event. However, this possibility is not at all surprising because prodromal-based pharmacological intervention in humans is often initiated during periadolescence or early adolescence, which represents a time window of significant ongoing brain development and maturation.43
The present study provides direct experimental evidence for this possibility by identifying numerous detrimental effects of the chronic exposures to antipsychotic or antidepressant medication during periadolescence on subsequent adult brain and behavioral functions in false-positive subjects (ie, offspring born to CON mothers).
Second, the low conversion rates from the initial prodromal to the full-blown psychotic stage may also undermine the evaluation and interpretation of possible beneficial effects of early pharmacotherapy in the preventive treatment of schizophrenia. Hence, even though a low conversion rate to psychosis may truly reflect positive benefits of the early pharmacological intervention, such seemingly beneficial effects may be occluded by presence of false-positive subjects whose prognosis would have been satisfactory even in the absence of any medication.8,9,16,17
Our experimental design is expected to yield results devoid of such interpretative problems because it allows an evaluation of such early pharmacological intervention within an explicit comparison between 2 distinct groups of subjects that can be prospectively identified as being predisposed to multiple schizophrenia-like adult behavioral abnormalities (ie, adult PolyI:C offspring) or not (ie, CON offspring). Against this background, our findings of beneficial effects of preventive medication readily support the hypothesis that early pharmacological intervention in psychosis-prone subjects can successfully block the conversion into a full-blown psychotic disorder.5–9
Interestingly, the data thus far available in humans suggest that such early pharmacological intervention is not effective for the prevention of the whole spectrum of psychosis-related abnormalities after treatment with one specific class of pharmacological compounds. For example, Cornblatt and colleagues9
recently reported that exposure to antidepressant drugs during the initial prodromal phase was only effective in preventing the emergence of 3 out of 5 positive symptoms. This is in agreement with the experimental data presented here, which suggest that early pharmacological intervention with distinct antipsychotic or antidepressant compounds leads only to a partial but not full blockade of further progression into the full-blown schizophrenia-related phenotype.
In a recent study, Tenn et al19
have explored a model of progressive behavioral/psychomotor sensitization in rats as a putative animal model of the prodromal state of schizophrenia. In this model, rats were treated with different regimes of AMPH to produce full behavioral sensitization (analogous to the full psychotic phenotype) or partial sensitization (analogous to the prodromal phenotype), and they were then treated with the typical and atypical antipsychotic drug HAL and CLZ, respectively, in order to mimic preventive pharmacological intervention. The authors showed that animals having experienced full sensitization displayed significant behavioral deficits implicated in schizophrenia, including reduced PPI, deficient LI, and enhanced sensitivity to acute AMPH treatment.19
On the other hand, animals subjected to a partial sensitization regimen showed only a muted phenotype, ie, they displayed potentiated AMPH sensitivity but normal PPI and LI.19
Most importantly, fully sensitized animals that received early preventive HAL or CLZ treatment did not progress from the “prodromal” to the full-blown phenotype when tested in a drug-free state.19
The outcomes of early preventive antipsychotic drug treatment as evaluated in the present study share some striking similarities with those yielded in the experimental model of partial AMPH sensitization in rats.19
However, the 2 models also critically differ in several aspects. Consistent with the present results, preventive HAL and CLZ treatment both restored LI abnormalities induced by the experimental manipulation (ie, AMPH sensitization or prenatal PolyI:C exposure) without affecting LI in CON subjects. In the AMPH-based model of the prodromal state of schizophrenia,19
both HAL and CLZ were similarly effective in blocking the emergence of PPI deficiency and AMPH hypersensitivity. Here, only periadolescent HAL (and FLX) but not CLZ exposure successfully prevented the prenatal PolyI:C-induced AMPH potentiation in adulthood (); and only CLZ and FLX but not HAL treatment during periadolescence normalized the prenatal PolyI:C-induced PPI deficits (). Another critical distinction between the 2 experimental models is that chronic antipsychotic drug exposure in CON animals (ie, SAL-treated subjects) did not exert any negative influences on PPI or sensitivity to acute AMPH challenge when tested in a drug-free state.19
Here, we clearly revealed such detrimental long-term effects of chronic antipsychotic or antidepressant drug exposure when given to CON animals (ie, offspring born to CON mothers). It is conceivable to explain these differences by the precise timing of the preventive pharmacological manipulation. Indeed, in our model, subjects were exposed to the preventive pharmacotherapy during periadolescent development, whereas all experimental manipulations were conducted during adulthood in the AMPH-based experimental model of the psychosis prodrome.19
Because preventive pharmacological intervention during the initial prodromal phase in humans is most often initiated in periadolescence or early adolescence, our model described here more closely mimics the human condition. This is therefore unlike the approach adopted by Tenn et al,19
in which all manipulations were conducted in adult subjects. Hence, the sensitivity of the prenatal PolyI:C model to detrimental behavioral effects of chronic pharmacotherapy in CON subjects represents an important improvement over previous models of prodromal-based preventive intervention in adulthood because it highlights some of the possible risk factors associated with unnecessary preventive pharmacotherapy in false-positive subjects.
One limitation of the present experimental evaluation of the effects of chronic pharmacotherapy for preventive reasons is that we only evaluated one specific dose for each drug. Periadolescent CLZ treatment at the selected dose here (15 mg/kg/day) led to a serum concentration of approximately 30 ng/ml after subchronic or chronic administration (). This is about 10 times lower compared with clinically effective serum concentrations after subchronic or chronic CLZ treatment in adult human patients.44–46
On the other hand, the daily administration of HAL (3 mg/kg/day) and FLX (20 mg/kg/day) led to serum concentrations of ~110 and 570 ng/ml, respectively, after subchronic treatment and to ~110 and 1030 ng/ml after chronic treatment (). For both drugs, these concentrations are 2–6 times higher than the usual concentrations targeted in humans.41,47
It is important to emphasize that the half-life times of many antipsychotic and antidepressant drugs in rodents are 4–6 times faster than in humans.41,45
Higher drug regimes are thus often needed in rodents relative to humans in order to obtain receptor occupancies that are comparable with those present during clinically effective pharmacotherapy in humans.45
Undoubtedly, a dose-response approach would be warranted in order to further confirm the present findings of both beneficial and detrimental effects of the early pharmacological interventions. Specifically, it would be of great interest to evaluate whether HAL and FLX treatment at lower doses may still exert preventive effects against the emergence of schizophrenia-related behavioral and pharmacological abnormalities without inducing significant brain and behavioral deficits when given to CON subjects and whether periadolescent administration of CLZ at higher doses may also induce negative behavioral effects in CONs.
Taken together, our results provide experimental evidence that early pharmacological intervention may provide a successful strategy for the prevention of multiple psychosis-related abnormalities in subjects predisposed to adult dysfunctions. Because the experiments reported here are based on prenatal infection-induced interference with normal brain development, the present findings may be especially relevant for subjects at high risk for schizophrenia following prenatal exposure to infection.48–50
Of equal importance are the findings that chronic antipsychotic or antidepressant drug treatment in false-positive subjects is associated with substantial risk for long-lasting brain and behavioral disturbances in adulthood. The present study thus also highlights the critical importance of targeting early preventive pharmacotherapy only to psychosis-prone individuals. This readily suggests the necessity for a careful examination of possible risks and benefits before initiating any early pharmacological intervention programs designed to reduce the incidence of schizophrenia and related disorders among high-risk individuals.