Depression is an affective disorder characterized by low mood and inability to experience pleasure as core symptoms (American Psychiatric Association, 2000). Risk factors for developing depression are increased with age (Tiemeier, 2003; Blazer and Hybels, 2005; McKinney et al., 2012) because the homeostatic reserves of the organism to overcome biological challenges are lower, thus increasing vulnerability (Toescu, 2005). The prevalence of depression in the general older population is about 8–18%, although higher rates (>30%) have been found in primary care services or nursing homes (Blazer, 2003; Luijendijk et al., 2008). Moreover, the total number of depressed individuals will probably increase along with the expected increase of aged populations in the next few years from 52 million in 2010 to 1.5 billion in 2050 (WHO, 2011). Depressed older patients are more likely to develop additional diseases and more severe symptomatology than young adults (YAs) (Gareri et al., 2000; Fiske et al., 2009; Hegeman et al., 2012), which might contribute toward the high rates of suicide among the elderly (Gottfries, 2001). These conditions underscore the relevance of mental health research for the aged population.
The effectiveness of antidepressants in older individuals has not been systematically assessed. The most commonly prescribed medications are the prototypical tricyclic antidepressants (TCA), such as desipramine (DMI) or imipramine, and the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (FLX) or paroxetine (Gareri et al., 2000; Coupland et al., 2011). The pharmacological targets of TCA are the norepinephrine and/or the serotonin transporters, but they can also bind to adrenergic α1 and histaminergic H1 receptors, leading to motor side-effects such as dizziness, drowsiness, and sedation (Owens et al., 1997; Gareri et al., 2000; Gillman, 2007). In contrast, SSRIs have low affinity for such receptors; thus, motor side-effects are not commonly reported (Gareri et al., 2000). Instead, SSRIs might produce nausea, diarrhea, and sexual dysfunction as a consequence of the activation of different serotonergic receptors (Owens et al., 1997; Gareri et al., 2000; Gillman, 2007). Unfortunately, the side-effects of antidepressants and other central nervous system drugs are increased in older patients (Turnheim, 2003; Trifirò and Spina, 2011), whereas their therapeutic effects have not been strongly supported. Although TCA and SSRIs are reported to be effective in clinical trials with older patients (Gareri et al., 2000; Salzman et al., 2002; Blazer, 2003), some authors have claimed that their effectiveness is reduced compared with YAs (Lenze et al., 2008; Sheffrin et al., 2009; Tedeschini et al., 2011). It is probable that such a decline begins at middle age (MA) as a modest reduction that becomes pronounced at senescence (Tedeschini et al., 2011), but studies testing this proposal have not been carried out.
Experiments in animals on this topic are scarce. Bourin and colleagues found that some antidepressants were less effective in 40-week-old mice compared with 4-week-old subjects (Bourin et al., 1998; David et al., 2001), whereas in another study, MA rats (12–15 months old) required a longer treatment than YAs (3–5 months old) to show the antidepressant-like response to citalopram (Herrera-Perez et al., 2010). These data support the hypothesis of a lower sensitivity to antidepressants with age; however, the lifespan of laboratory rodents is about 24–34 months (Nadon, 2006). Thus, information from senescent (SE) animals is strongly required.
The forced-swim test (FST) is a behavioral procedure aimed at detecting the antidepressant-like effect of drugs, hormones, or nonpharmacological treatments (Cryan et al., 2005). The model is based on the observation that animals forced to swim in a restricted space eventually cease their attempts to escape and become immobile (Porsolt et al., 1977). Immobility is considered a depressive-like behavior and is reduced by antidepressants (Porsolt et al., 1977; Cryan et al., 2005). The FST has been characterized for different strains and biological conditions such as sex and hormonal state (Lopez-Rubalcava and Lucki, 2000; Drossopoulou et al., 2004). Additional assessments, such as locomotor activity and motor coordination, might be useful for refining the interpretation of the FST; in turn, they are core procedures in safety pharmacology studies (Porsolt et al., 2002) that become valuable when testing aged organisms.
In this study, we compared the effectiveness of the antidepressants DMI and FLX in YAs (3–5 months old), MA (12–15 months old), and SE (23–25 months old) male rats by using the FST. We also assessed locomotor activity and motor coordination to detect putative motor side-effects. It was expected that the antidepressant-like effect of both DMI and FLX would decrease at MA and, to a larger extent, at senescence, whereas motor side-effects would probably increase with age, especially for DMI.
We used male Wistar rats of three different ages: YA (3–5 months old), MA (12–15 months old), and SE (23–25 months old). They were obtained from the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM) vivarium and were group housed in polycarbonate cages (60×40×20 cm, 3–4/cage), under controlled temperature and humidity conditions, and a light/dark cycle 12/12 h (lights on at 10:00 h). All animals were allowed free access to standard Purina rodent chow and tap water, and their general health state was monitored periodically. Rats showing illnesses such as tumors or respiratory diseases were not included in the experiments. The study design was adjusted following the three Rs of the use of animals in experimental research, that is, replacement, reduction, and refinement (Baumans, 2004). Official national policies for the use and care of laboratory animals (NOM-062-ZOO-1999) were followed and procedures were approved by the local ethical committees (CINVESTAV-IPN and INPRFM).
Rats from each age (YA n=50, MA n=64, SE n=59) were distributed randomly into independent groups to receive saline [vehicle (VEH)], DMI (5, 10, and 20 mg/kg), or FLX (5, 10, and 20 mg/kg). Dose ranges were established from a previous study showing their effectiveness in YA male rats (Martinez-Mota and Fernández-Guasti, 2004). In addition, locomotor activity and motor coordination were assessed by the open-field test (OFT) and rota-rod test, performed 10 and 5 min, respectively, before the FST test session.
Rats were placed individually into an actimeter (45×45×20 cm, Panlab 8811-IR; Panlab, Barcelona, Spain), which registered their spontaneous ambulatory activity by infrared sensors attached to a data transfer software (Sedacom; Panlab, Barcelona, Spain). The field was wiped with a cleaning solution and completely dried before use. Results are expressed as the mean±SEM of ambulatory movements during the test.
Each rat was placed on a rotating cylinder (7 cm diameter, 11 rpm) and its capacity to keep walking for 5 min was registered (test session). Previously, they were trained for 3 consecutive days, one session daily (10, 5, and 5 min, respectively) (Fernández-Guasti and Lopez-Rubalcava, 1998). When a rat dropped from the rota-rod, it was placed again on the cylinder and the session was continued; however, when it fell five times in a minute or did not show intentional movements to walk, the session was stopped and the training was continued the next day. If these conditions occurred on the test day, the rat was judged incapable of performing the test. For each group, we obtained the percentage of rats able to perform the test.
We used the modified version of the FST reported by Detke et al. (1995); briefly, rats were placed individually in a glass cylinder (40 cm high, 20 cm diameter) filled with fresh water (30 cm, 23±2°C) and were forced to swim. Two sessions were conducted: a pretest (15 min) for inducing a depressive-like behavior (immobility) and the test session (5 min), performed 24 h later, to assess the antidepressant-like effect of drugs. After swimming, rats were gently dried with towels and placed in a heated cage (15 min) to recover before being returned to their home cages. Test sessions were video-recorded and were then analyzed separately in a blinded manner by two experimenters. For the analysis, the instantaneous sampling technique was used (Detke et al., 1995), where the animal was rated as immobile or not every 5 s for a total of 60 sampling periods. Immobility was recorded when the rat showed only the necessary movements to keep its head above the water (Detke et al., 1995). Inter-rater and intrarater reliability were at least r=0.87 for scoring immobility behavior. Results are expressed as the total number of immobility counts (mean±SEM).
Desipramine hydrochloride (DMI; Sigma-Aldrich, St. Louis, Missouri, USA) and fluoxetine hydrochloride (FLX, kindly provided by Laboratorio Médico Químico Biológico, S.A. de C.V.) were dissolved in VEH (physiological saline solution, 0.09%) and administered subcutaneously in a subchronic schedule, consisting of three injections over 24 h (24, 5, and 1 h) before the FST (Detke et al., 1995). Solutions were freshly prepared before use and were administered in a volume of 2 ml/kg.
Immobility scores (FST) and locomotor activity (OFT) were analyzed using a three-way analysis of variance with the factors age (YA, MA, and SE), drug (DMI and FLX), and dose (0, 5, 10, and 20 mg/kg), followed by Tukey’s comparisons. Then, DMI and FLX groups were analyzed separately to determine differences by age and dose with a two-way analysis of variance and the Tukey post-hoc test. For motor coordination, we used the Fisher exact test to compare the percentages of animals able to perform the test, between drug-treated rats and the age-matched VEH group, as well as the effect of each dose at the three different ages. Data were analyzed using Sigma Plot (version 11.0; Systat Software Inc, San Jose, California, USA). All significant values were set at P value less than 0.05.
The antidepressant-like effect of drugs was significantly influenced by the interaction of the factors age×drug×dose (F 6, 182=2.584, P=0.02). Aging itself reduced the immobility behavior (VEH groups), being significant for SE rats (P<0.02 and <0.001 vs. YA and MA, respectively; compare white bars in Fig. 1).
The antidepressant-like effect of DMI was significantly influenced by the dose (F 3, 81=5.09, P=0.005) and the age×dose interaction (F 6, 81=5.86, P<0.001). Effective doses in YA rats were 5 and 10 mg/kg, whereas in MA, they were 10 and 20 mg/kg (Fig. 1a). Thus, a shift to the right in the dose–response curve was produced. Remarkably, DMI did not reduce immobility in SE rats; instead, it was augmented at 10 mg/kg.
The antidepressant-like effect of FLX was strongly influenced by the dose (F 3, 100=7.88, P<0.001) and the age×dose interaction (F 6, 100=5.49, P<0.001), and a tendency was found for an effect of age (F 2, 100=2.961, P=0.056). In YA rats, FLX was effective at 10 mg/kg, whereas at 20 mg/kg the immobility was reduced in a nonsignificant manner (P=0.15). In MA rats, effective doses were 10 and 20 mg/kg (Fig. 1b). As with DMI, FLX did not produce an antidepressant-like effect in SE rats and immobility was increased at 5 mg/kg.
Locomotor activity was influenced by the age×drug×dose interaction (F 6, 182=2.32, P<0.05). In VEH groups, YA rats were more active than MA and SE (P<0.01 and <0.001, respectively), whereas there were no significant differences between MA and SE.
For DMI, we found a significant effect of age (F 2, 81=13.14, P<0.001), dose (F 3, 81=27.31, P<0.001), and the age×dose interaction (F 6, 81=2.34, P<0.05). Locomotor activity was decreased by DMI at 5, 10, and 20 mg/kg in YA rats, and by 10 and 20 mg/kg in MA and SE rats (Table 1).
For FLX, a significant effect was found for age (F 2, 81=8.72, P<0.001), dose (F 3, 81=11.39, P<0.001), and the age×dose interaction (F 6, 81=2.19, P<0.05). In the YA group, ambulatory movements decreased after FLX at 10 and 20 mg/kg, whereas in MA and SE rats, a decrease was produced at 20 mg/kg. Importantly, locomotor activity was not increased by any treatment.
Aging was associated with a reduction in motor coordination. In VEH groups, all YA and most MA (90%) rats were able to perform the test, whereas only 57% of SE performed it successfully. This percentage was significantly different from YA rats (P<0.05), but not from MA rats (Fig. 2).
Motor coordination was impaired by DMI in MA and, remarkably, in SE rats. In MA rats, motor coordination was completely blunted at 20 mg/kg of DMI (0%, P<0.002). In SE rats, the execution capacity was completely abolished by 20 mg/kg (0%, P<0.05) (Fig. 2a). It was also found that motor coordination impairments produced by DMI increased with aging because the lowest dose (5 mg/kg) affected only SE rats (P<0.05 and <0.001 vs. YA and MA, respectively), whereas 10 mg/kg affected MA and SE (NS and P<0.02 vs. YA, respectively). Remarkably, the highest dose (20 mg/kg) completely impaired motor coordination in both MA and SE rats (P<0.02 and <0.005 vs. YA), but not in YA rats.
In contrast to the actions of DMI on performace in the rota-rod test, FLX did not decrease motor coordination at senescence (Fig. 2b).
The current study shows that the antidepressant-like effect of DMI and FLX is reduced during the aging process, but this does not occur in their motor side-effects. At MA, we found a shift to the right in the dose–response curve of DMI, compared with YA, whereas at senescence neither drug was effective. In terms of motor side-effects, locomotor activity was similarly decreased by DMI and FLX at all ages, whereas motor coordination was impaired only with DMI, especially in SE rats. Therefore, side-effects do not explain the reduced efficacy of antidepressants. These findings are in line with clinical observations of reduced antidepressant effectiveness in older patients (Lenze et al., 2008; Sheffrin et al., 2009; Tedeschini et al., 2011) as well as increased side-effects of TCA (Mottram et al., 2006).
The present study provides strong evidence that prototypical antidepressants fail to produce an antidepressant-like effect at senescence in the rat FST. Moreover, it shows that MA animals are still sensitive to such drugs, but higher doses are required. These findings are consistent with a meta-analysis of placebo-controlled randomized trials (Tedeschini et al., 2011) where antidepressants were more effective than placebo in YAs and, to a lesser extent, in patients aged 55 years or older. However, the antidepressant and placebo groups were indistinguishable in the elderly subset (>65 years). Therefore, response to antidepressant drugs decrease progressively with aging and might be abolished at senescence.
Here, both DMI and FLX exerted an antidepressant-like effect in MA rats. This observation is in partial agreement with studies in mice, where TCA such as DMI and imipramine were effective in MA subjects, whereas SSRIs as paroxetine, citalopram, and fluvoxamine (but not sertraline) were not (Bourin et al., 1998; David et al., 2001). This discrepancy may be associated with structural, chemical, and pharmacological differences among SSRIs (Owens et al., 1997, 2001); moreover, sensitivity to serotonergic drugs in the FST has been reported to be variable in some mice strains (Petit-Demouliere et al., 2005; Bogdanova et al., 2013). Studies in MA rats agree with our findings; for example, Sun and Alkon (2008) reported that young (4 weeks old) and older (3, 6, and 14 months old) animals are similarly sensitive to the antidepressant-like effect of imipramine in the novel open-space swim test. In another study, the SSRI citalopram was effective in young and MA rats (around 4 and 14 months, respectively) in the chronic mild stress (CMS) paradigm, although MA animals required more days of treatment to show the antidepressant-like effect (Herrera-Perez et al., 2010). The study supports the position that MA animals are still sensitive to antidepressants and provides additional information on the profile of temporal effects. Unfortunately, SE rats (24 months) could not withstand the CMS protocol and died during a pilot study (Herrera-Perez and Martinez-Mota, unpublished data), indicating the frailty of very old rodents, as well as some limitations of the CMS model. Taken together, these studies support our findings of preserved sensitivity of MA rats to antidepressants. In clinical studies, both kinds of drugs are reported to be similarly effective in old patients (Salzman et al., 2002; Blazer, 2003), although TCA seem to be more effective than SSRIs for treating melancholic and psychotic depression (Rudorfer and Potter, 1999; Parker, 2002; Joyce et al., 2003; Gillman, 2007). However, these data must be interpreted with caution because the populations included were MA and SE patients, not stratified by age.
Analysis of motor parameters showed that the antidepressant-like effect of drugs was not a consequence of unspecific motor activation, excluding the possibility of false-positive interpretations. Indeed, locomotor activity was decreased by DMI and FLX, as reported for most antidepressants (Tucker and File, 1986; Cryan et al., 2005), whereas it was not increased by any treatment. Importantly, drugs produced an antidepressant-like effect despite some motor coordination impairments, such as that caused by DMI (20 mg/kg) in MA rats. In turn, the lack of an antidepressant-like effect of FLX in SE rats was not a consequence of motor disability.
The locomotor activity could alternatively be interpreted as influenced by experimental anxiety levels. However, increased experimental anxiety is inferred from a decreased activity in the central area of the field without modifying total locomotion or vertical exploration (Prut and Belzung, 2003); thus, general locomotion does not vary directly as a function of experimental anxiety. Accordingly, the anxiolytic drug diazepam (0.25 mg/kg, 30 min before the test) did not modify general locomotor activity in mice compared with a VEH-treated group (Strekalova et al., 2005). Another important issue is the test duration. Temporal profiles of locomotor activity in the OFT show that rats are most active in the first 5 to 10 min, and thereafter, activity decreases to return to basal conditions (Brenes et al., 2009; Del Arco et al., 2011; Leke et al., 2012). Because the basal activity of MA and SE rats was low, a longer session was not likely to provide significant information. Accordingly, motor impairments in aged rats have been detected by the OFT in a 3-min test (Altun et al., 2007).
Pharmacokinetic changes produced by age modify the final drug effects. The most significant change is a reduction of renal excretion, caused by a deficient glomerular filtration (Turnheim, 2003; Mangoni and Jackson, 2004). As a consequence, drug serum levels tend to increase, producing a stronger pharmacological effect. The opposite was found here for the antidepressant-like effect in aged subjects, although such pharmacokinetic changes might explain the increased side-effects on motor functions.
In agreement with this study, an age-related reduction in effectiveness has been reported for other drugs acting on the central nervous system. As an example, metrifonate – an acetylcholinesterase inhibitor – was effective in 3 and 23-month-old rats, but not in 27-month-old rats (Riekkinen et al., 1996). Similarly, the anxiolytic-like effect of diazepam and the anticompulsive-like action of FLX were absent in 10–14-month-old rats (Olvera-Hernández and Fernández-Guasti, 2011; Olvera-Hernández et al., 2013), although they produced some motor coordination impairments. In an interesting study, Wikinski et al. (2001) reported that 24-month-old rats were insensitive to the anxiolytic-like effect of diazepam, which was also ineffective for reducing the chloride uptake induced by GABA in neurons in vitro (Wikinski et al., 2001), showing that age-related pharmacodynamic changes can be reflected in deficits in behavioral tests. The main pharmacological targets of antidepressants are the serotonin and norepinephrine pathways that are deteriorated in aged subjects (Lawlor et al., 1989; Yau et al., 1999; Hussain and Mitra, 2000; Ishida et al., 2000; Shirokawa et al., 2000; Van Dyck et al., 2000; Ishida et al., 2001; Kakiuchi et al., 2001; Duncan and Hensler, 2002; Yamamoto et al., 2002; Shirokawa et al., 2003). This deterioration may be a potential mechanism to explain the reduced efficacy of antidepressants.
In addition, serotonergic and noradrenergic activities are favored by adequate levels of sexual hormones such as testosterone. When male rats are gonadectomized, the expression of the serotonin transporter mRNA is reduced in the raphe nuclei (Fink et al., 1999; McQueen et al., 1999) and animals are insensitive to the antidepressant-like effect of DMI or FLX in the FST (Martinez-Mota and Fernández-Guasti, 2004). Levels of testosterone in rats decrease with aging (Carvalho et al., 1988; Bonavera et al., 1997; Wu et al., 2009); thus, it is feasible that the chronic androgen deficiency in SE rats plays a role in the lack of effect of DMI and FLX. Ongoing experiments are exploring this hypothesis. Moreover, future studies are required to detect whether other side-effects contribute toward the reduced effectiveness of antidepressants, for example, sleep disturbances.
In conclusion, it was found that aging decreases the sensitivity of male rats to the antidepressant-like effect of DMI or FLX in the FST. In addition, motor side-effects were increased with DMI. This study might be useful for developing strategies to achieve clinical recovery from depressive symptoms in aged patients.
The authors thank M.V.Z. Mario Aguilar for his invaluable veterinary support and expert suggestions; Sergio Marquez for technical assistance and animal care; and Dr Jorge Ocampo from Bioquimed Laboratories for fluoxetine donation. This study was partially supported by the National Institute of Psychiatry Ramón de la Fuente Muñiz (grant 3370.0) and by a CONACYT fellowship to M.O.N. (no. 38462).
Conflicts of interest
There are no conflicts of interest.
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