Metabolism and Pharmacokinetics of Selective Serotonin Reuptake Inhibitors

1. Five drugs with the predominant pharmacologic effect of inhibiting the neuronal reuptake of serotonin are available worldwide for clinical use. This class of psychoactive drugs, known as selective serotonin reuptake inhibitors (SSRIs), is comprised of fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram.2. The SSRIs appear to share similar pharmacodynamic properties which translate to efficacy in the treatment of depression and anxiety syndromes. The drugs are differentiated by their pharmacokinetic properties with regard to stereochemistry, metabolism, inhibition of cytochrome enzymes, and participation in drug–drug interactions. Studies focusing on the relationship of plasma drug concentration to therapeutic and adverse effects have not confirmed the value of plasma concentration monitoring.3. This review summarizes the metabolism and relevant pharmacokinetic properties of the SSRIs.     

Selective Serotonin Reuptake Inhibitors Potentiate the Rapid Antidepressant-Like Effects of Serotonin4 Receptor Agonists in the Rat

Background

We have recently reported that serotonin₄ (5-HT₄) receptor agonists have a promising potential as fast-acting antidepressants. Here, we assess the extent to which this property may be optimized by the concomitant use of conventional antidepressants.

Methodology/Principal Findings

We found that, in acute conditions, the 5-HT₄ agonist prucalopride was able to counteract the inhibitory effect of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram on 5-HT neuron impulse flow, in Dorsal Raphé Nucleus (DRN) cells selected for their high (>1.8 Hz) basal discharge. The co-administration of both prucalopride and RS 67333 with citalopram for 3 days elicited an enhancement of DRN 5-HT neuron average firing rate, very similar to what was observed with either 5-HT₄ agonist alone. At the postsynaptic level, this translated into the manifestation of a tonus on hippocampal postsynaptic 5-HT_1A receptors, that was two to three times stronger when the 5-HT₄ agonist was combined with citalopram. Similarly, co-administration of citalopram synergistically potentiated the enhancing effect of RS 67333 on CREB protein phosphorylation within the hippocampus. Finally, in the Forced Swimming Test, the combination of RS 67333 with various SSRIs (fluvoxamine, citalopram and fluoxetine) was more effective to reduce time of immobility than the separate administration of each compound.

Conclusions/Significance

These findings strongly suggest that the adjunction of an SSRI to a 5-HT₄ agonist may help to optimize the fast-acting antidepressant efficacy of the latter.     

Serotonin and Noradrenaline Reuptake Inhibitors Improve Micturition Control in Mice

Poor micturition control may cause profound distress, because proper voiding is mandatory for an active social life. Micturition results from the subtle interplay of central and peripheral components. It involves the coordination of autonomic and neuromuscular activity at the brainstem level, under the executive control of the prefrontal cortex. We tested the hypothesis that administration of molecules acting as reuptake inhibitors of serotonin, noradrenaline or both may exert a strong effect on the control of urine release, in a mouse model of overactive bladder. Mice were injected with cyclophosphamide (40 mg/kg), to increase micturition acts. Mice were then given one of four molecules: the serotonin reuptake inhibitor imipramine, its metabolite desipramine that acts on noradrenaline reuptake, the serotonin and noradrenaline reuptake inhibitor duloxetine or its active metabolite 4-hydroxy-duloxetine. Cyclophosphamide increased urine release without inducing overt toxicity or inflammation, except for increase in urothelium thickness. All the antidepressants were able to decrease the cyclophosphamide effects, as apparent from longer latency to the first micturition act, decreased number of urine spots and volume of released urine. These results suggest that serotonin and noradrenaline reuptake inhibitors exert a strong and effective modulatory effect on the control of urine release and prompt to additional studies on their central effects on brain areas involved in the social and behavioral control of micturition.     

Successful Treatment of Epilepsy with Serotonin Reuptake Inhibitors: Proposed Mechanism

The widely used antidepressants Specific Serotonin Reuptake Inhibitors (SSRI) have been tried with success as anticonvulsants in cases of nonsymptomatic epilepsy. This attempt was performed on the basis of experimental data suggesting the involvement of impairments of the serotonin system in the genesis of epilepsy. This overview summarizes the clinical data and presents biochemical and neurochemical evidences suggesting the mechanism of the therapeutic effects of SSRI in nonsymptomatic epilepsy. In particular, studies on blood-borne neutral amino acids and platelet serotonin transporter (SERT) in epileptics suggest: (a) That a decreased brain availability of tryptophan may be related to some types of epilepsy. (b) That reduction of the density of SERT may be a homeostatic reaction in the brain following epileptic seizures.     

Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons

The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT_1A and α₂-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of G_i protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT_1A and α₂-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.     

Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT_1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT_1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT_1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT_1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT_1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder.     

Effects of Adenosine Receptor Subtypes on Hippocampal Extracellular Serotonin Level and Serotonin Reuptake Activity

Abstract: To clarify the effects of adenosine receptor subtypes (A₁, A₂, and A₃) on hippocampal serotoninergic function, hippocampal extracellular serotonin (5-HT) levels were determined by in vivo microdialysis in freely moving rats under various conditions. Both adenosine and an adenosine A₁ receptor agonist, 2-chloro-N⁶-cyclopentyladenosine, decreased extracellular 5-HT levels, whereas an adenosine A₁ receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), and caffeine increased these levels. A selective A_2A receptor agonist (CGS-21680), an adenosine A₂ receptor agonist (PD-125944), an adenosine A₂ receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), and an adenosine A₃ receptor agonist, N⁶-2-(4-aminophenyl)ethyladenosine (APNEA), did not affect extracellular 5-HT levels. When the adenosine A₁ receptor was blocked by CPT, the hippocampal extracellular 5-HT level was increased by adenosine, CGS-21680, and PD-125944, and decreased by caffeine, DMPX, and APNEA. When both adenosine A₁ and A₂ receptors were blocked by CPT and DMPX, the extracellular 5-HT level was decreased by adenosine, caffeine, and APNEA. The hippocampal extracellular 5-HT level was not affected by administration of APNEA alone, but was decreased by this agent when the adenosine A₁ receptor was blocked, irrespective of whether the adenosine A₂ receptor was functional. These inhibitory effects of adenosine, caffeine, and APNEA on extracellular 5-HT levels, during both adenosine A₁ and A₂ receptor blockade, were inhibited by selective 5-HT reuptake inhibitors. These results indicate that the stimulatory effects of the adenosine A₂ receptor and the inhibitory effects of the A₃ receptor on hippocampal extracellular 5-HT levels are masked by the inhibitory effects of the adenosine A₁ receptor.     

The Effect of Antenatal Depression and Selective Serotonin Reuptake Inhibitor Treatment on Nerve Growth Factor Signaling in Human Placenta

Depressive symptoms during pregnancy are common and may have impact on the developing child. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressant treatment, but unfortunately, these treatments can also negatively affect the behavioral development and health of a child during pregnancy. In addition, serotonin (5-HT) exerts neurotrophic actions with thus far not fully known effects in the offspring. The neurotrophic growth factor (NGF) is involved in neuronal cell survival and differentiation, and altered placenta levels have been found to increase the risk for pregnancy complications, similar to those found in women treated with SSRIs. We therefore investigated whether the NGF signaling pathway was altered in the placenta from women treated with SSRIs (n = 12) and compared them with placenta from depressed (n = 12) and healthy mothers (n = 12). Results from immunohistochemical stainings revealed that placental NGF protein levels of SSRI-treated women were increased in both trophoblasts and endothelial cells compared with depressed and control women. In addition, downstream of the NGF receptor TrkA, increased levels of the signaling proteins ROCK2 and phosphorylated Raf-1 were found in stromal cells and a tendency towards increased levels of ROCK2 in trophoblasts and endothelial cells in SSRI-treated women when compared to healthy controls. SSRI-treated women also displayed increased levels of phosphorylated ROCK2 in all placental cell types studied in comparison with depressed and control women. Interestingly, in placental endothelial cells from depressed women, NGF levels were significantly lower compared to control women, but ROCK2 levels were increased compared with control and SSRI-treated women. Taken together, these results show that the NGF signaling and downstream pathways in the placenta are affected by SSRI treatment and/or antenatal depression. This might lead to an altered placental function, although the clinical relevance of our findings still needs to be investigated.     

National Cohort Study of Suicidality and Violent Criminality among Danish Immigrants

Background

Immigrant populations in western societies have grown in their size and diversity yet evidence is incomplete for their risks of suicidality and criminal violence. We examined these correlated harmful behaviours in a national cohort.

Aims

(i) Compare absolute risk between first and second generation immigrants, foreign-born adoptees and native Danes by plotting cumulative incidence curves to onset of early middle age; (ii) estimate sex-specific relative risks for these immigrant type subgroups vs. native Danes; (iii) examine effect modification by higher vs. lower socio-economic status.

Methods

In a cohort of over two million persons, attempted suicides and violent crimes were investigated using data from multiple interlinked registers. We plotted sex-specific cumulative incidence curves and estimated incidence rate ratios.

Results

In the whole study cohort, 1414 people died by suicide, 46,943 attempted suicide, and 51,344 were convicted of committing a violent crime. Among all immigrant subgroups combined, compared with native Danes, relative risk of attempted suicide was greater in female immigrants (incidence rate ratio, 1.59; 95% confidence interval: CI 1.54-1.64) than in male immigrants (1.26; CI 1.20-1.32), and vice versa for relative risk of violent offending in male immigrants (2.36; CI 2.31-2.42) than in female immigrants (1.74; CI 1.62-1.87). Risk for both adverse outcomes was significantly elevated in virtually every gender-specific immigrant type subgroup examined. Violent crime risk was markedly raised in first generation immigrant males and in the Danish born male children of two immigrant parents. However, male immigrants of lower social status had lower risk of attempted suicide than their native Danish peers.

Conclusion

Young immigrants of both first and second generation status face serious challenges and vulnerabilities that western societies need to urgently address. Relative risk patterns for these adverse outcomes vary greatly between the genders and also by socioeconomic status. This high degree of heterogeneity points to the existence of modifiable factors that are amenable to positive change and a potential for effective intervention.     

Effects of the Selective Serotonin Reuptake Inhibitor Fluoxetine on Social Behaviors in Male and Female Prairie Voles (Microtus ochrogaster)

The selective serotonin reuptake inhibitor fluoxetine modifies social behavior in a number of species, including humans. Because the neural substrates for social behavior in prairie voles are sexually dimorphic, we tested whether the effects of fluoxetine on these behaviors differ by sex. Parental and pair-bonded voles were chronically treated with fluoxetine or saline and subsequently tested for parental responsiveness. Fluoxetine-treated animals displayed a longer latency to exhibit parental responsiveness than did saline-treated controls (p< 0.02), but they did not differ in other aspects of parental care. There were no sex differences in the effects of fluoxetine on parental behavior. After completion of the tests for parental behavior, the subjects were tested for aggressive behavior using the resident–intruder paradigm. Fluoxetine-treated males displayed less aggressive behavior than their saline-treated counterparts (p< 0.02). Although we did not find any effects of fluoxetine on aggressive behavior in females, no significant interaction was found between sex and treatment. Fluoxetine did not alter nonsocial behaviors. The findings suggest that serotonin influences social behavior in prairie voles.     

Breastfeeding and Snoring: A Birth Cohort Study

Objective

To investigate the relationship between breastfeeding and snoring in childhood.

Methods

In a cohort of children with a family history of asthma who were recruited antenatally we prospectively recorded data on infant feeding practices throughout the first year of life. Snoring status and witnessed sleep apnea were measured at age 8 years by parent-completed questionnaire. Associations were estimated by logistic regression with, and without, adjustment for sets of confounders designed to exclude biasing effects.

Results

Habitual snoring was reported in 18.8% of the sample, and witnessed apnea in 2.7%. Any breastfeeding for longer than one month was associated with a reduced risk of habitual snoring at age 8 (adjusted OR 0.48, 95% CI 0.29 to 0.81) and duration of breastfeeding was inversely associated with the prevalence of habitual snoring (adjusted OR 0.79, 95% CI 0.62 to 1.00). Any breastfeeding for longer than 1 month was associated with a lower risk of witnessed sleep apnea (adjusted OR 0.17, 95% CI 0.04 to 0.71). The protective associations were not mediated by BMI, current asthma, atopy or rhinitis at age 8 years.

Conclusions

Breastfeeding for longer than one month decreases the risk of habitual snoring and witnessed apneas in this cohort of children with a family history of asthma. The underlying mechanism remains unclear but the finding would be consistent with a beneficial effect of the breast in the mouth on oropharyngeal development with consequent protection against upper airway dysfunction causing sleep-disordered breathing.     

Viral Co-infection and Leprosy Outcomes: A Cohort Study

Background

The role of the host immunity in determining leprosy clinical forms and complications is well recognized, implying that changes in the immune status may interfere with several aspects of the disease. Therefore, we hypothesized that the presence of viral co-infections and associated immunological changes will have a clinical impact on leprosy outcomes. The aim of our study was to determine the clinical impact of human immunodeficiency virus (HIV), human T cell lymphotrophic virus type 1 (HTLV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection on the development of reactions, neuritis, neuropathy and relapses.

Methodology/Principal Findings

Cohort study in 245 leprosy subjects from Bahia, Brazil. Patients were followed from the time of diagnosis until at least the end of multidrug therapy. Viral co-infection was detected in 36 out of the 245 patients (14.7%). Specific co-infection rates were 10.6% for HBV, 2.9% for HIV, 2.5% for HTLV-1 and 0.8% for HCV. All four groups of co-infected patients had higher rates of neuritis and nerve function impairment compared to non co-infected leprosy subjects. The relapse rate was also higher in the co-infected group (8.3%) versus patients without co-infection (1.9%); relative risk 4.37, 95% confidence interval 1.02–18.74.

Conclusions/Significance

Leprosy patients should be screened for HBV, HCV, HIV and HTLV-1 co-infections. Besides contributing to better health care, this measure will facilitate the early detection of severe complications through targeting of higher risk patients.     

Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study

Background

Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.

Methods and Findings

We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.

Conclusions

Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing. Please see later in the article for the Editors'' Summary     

10-y Risks of Death and Emergency Re-admission in Adolescents Hospitalised with Violent,Drug- or Alcohol-Related,or Self-Inflicted Injury: A Population-Based Cohort Study

Background

Hospitalisation for adversity-related injury (violent, drug/alcohol-related, or self-inflicted injury) has been described as a “teachable moment”, when intervention may reduce risks of further harm. Which adolescents are likely to benefit most from intervention strongly depends on their long-term risks of harm. We compared 10-y risks of mortality and re-admission after adversity-related injury with risks after accident-related injury.

Methods and Findings

We analysed National Health Service admissions data for England (1 April 1997–31 March 2012) for 10–19 y olds with emergency admissions for adversity-related injury (violent, drug/alcohol-related, or self-inflicted injury; n = 333,009) or for accident-related injury (n = 649,818). We used Kaplan–Meier estimates and Cox regression to estimate and compare 10-y post-discharge risks of death and emergency re-admission. Among adolescents discharged after adversity-related injury, one in 137 girls and one in 64 boys died within 10 y, and 54.2% of girls and 40.5% of boys had an emergency re-admission, with rates being highest for 18–19 y olds. Risks of death were higher than in adolescents discharged after accident-related injury (girls: age-adjusted hazard ratio 1.61, 95% CI 1.43–1.82; boys: 2.13, 95% CI 1.98–2.29), as were risks of re-admission (girls: 1.76, 95% CI 1.74–1.79; boys: 1.41, 95% CI 1.39–1.43). Risks of death and re-admission were increased after all combinations of violent, drug/alcohol-related, and self-inflicted injury, but particularly after any drug/alcohol-related or self-inflicted injury (i.e., with/without violent injury), for which age-adjusted hazard ratios for death in boys ranged from 1.67 to 5.35, compared with 1.25 following violent injury alone (girls: 1.09 to 3.25, compared with 1.27). The main limitation of the study was under-recording of adversity-related injuries and misclassification of these cases as accident-related injuries. This misclassification would attenuate the relative risks of death and re-admission for adversity-related compared with accident-related injury.

Conclusions

Adolescents discharged after an admission for violent, drug/alcohol-related, or self-inflicted injury have increased risks of subsequent harm up to a decade later. Introduction of preventive strategies for reducing subsequent harm after admission should be considered for all types of adversity-related injury, particularly for older adolescents.     

New Selective Growth Inhibitors of Sphaerotilus natans, Anslimins A and B

Selective growth inhibitors of Sphaerotilus natans were detected in the culture broths of several strains of Streptomyces. Anslimins A and B were isolated from the culture broth of Streptomyces oganonensis by adsorption on resinous adsorbent followed by elution with 50% aqueous acetone. The A and B components were then separated by cellulose powder chromatography. Physicochemical parameters of anslimins A and B revealed that these compounds are new peptide-containing structures. Anslimins A and B inhibited growth of S. natans at 0.78 and 0.39 μg/ml, respectively, but showed no activity against any of the other test microorganisms at 100 to 200 mg/ml. The anslimins had no harmful effect on guppies at a concentration of 100 mg/liter.     

Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study

Background

Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia.

Methods and Findings

We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3∶1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29–3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18–4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16–4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy.

Conclusions

Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians. Please see later in the article for the Editors'' Summary     

Effects of Selective Phosphodiesterases-4 Inhibitors on Learning and Memory: A Review of Recent Research

Phosphodiesterase-4 (PDE-4) regulates the intracellular level of cyclic adenosine monophosphate. Recent studies demonstrated that PDE-4 inhibitors can counteract deficits in long-term memory caused by aging or increased expression of mutant forms of human amyloid precursor proteins, and can influence the process of memory function and cognitive enhancement. Therapeutics, such as ketamine, a drug used in clinical anesthesia, can also cause memory deficits as adverse effects. Targeting PDE-4 with selective inhibitors may offer a novel therapeutic strategy to prevent, slow the progress, and, eventually, treat memory deficits.