Seizure activity and individual vulnerability on first-episode interictal psychosis in epilepsy.

OBJECTIVE: Despite a theoretical consensus that interictal psychosis (IIP) is related to various epilepsy-related factors, the impact of seizure activity on development of IIP remains inconclusive. This is the first controlled study using quantitative seizure-activity measures at the onset of IIP. METHODS: One hundred and eighty-one patients with epilepsy who exhibited first-episode IIP (IIP group) and 427 patients with epilepsy without psychotic episodes (control group) were enrolled. The control group was matched for age, epilepsy type, and duration of epilepsy. The two seizure-activity indices (seizure frequency at the time of onset of first-episode IIP and the number of seizures before the onset of IIP) were evaluated and compared between the IIP and control groups. Logistic regression analysis was used for extracting risk variables to develop first-episode IIP. RESULTS: The sum of previous seizures was greater in the IIP than in control groups. This was particularly the case in the patients with partial epilepsies (PE). Higher seizure frequency in the patients with PE was associated with the development of first-episode IIP while no association was found in the whole cohort or in the patients with generalized epilepsies (GE). Subsequent multivariate analysis revealed the sum of previous seizures and family history of psychosis as risk variables to first-episode IIP. CONCLUSIONS: The accumulation of seizure-related damages and family history of psychosis is associated with the onset of IIP episodes, particularly in the patients with PE. Seizure activity and individual vulnerability to psychosis are likely to be interacted for as the development of IIP in patients with epilepsy.

Zinc-related actions of sublethal levels of benzalkonium chloride: Potentiation of benzalkonium cytotoxicity by zinc.

Benzalkonium chloride (BZK) is a common preservative used in pharmaceutical and personal care products. ZnCl2 was recently reported to significantly potentiate the cytotoxicity of some biocidal compounds. In the present study, therefore, we compared the cytotoxic potency of BZK and then further studied the Zn2+-related actions of the most cytotoxic agent among BZK, using flow cytometric techniques with appropriate fluorescent probes in rat thymocytes. Cytotoxicity of benzylcetyldimethylammonium (BZK-C16) was more potent that those of benzyldodecyldimethylammonium and benzyldimethyltetradecylammonium. ZnCl2 (1-10 µM) significantly potentiated the cytotoxicity of BZK-C16 at a sublethal concentration (1 µM). The co-treatment of cells with 3 µM ZnCl2 and 1 µM BZK-C16 increased the population of both living cells with phosphatidylserine exposed on membrane surfaces and dead cells. BZK-C16 at 0.3-1.0 µM elevated intracellular Zn2+ levels by increasing Zn2+ influx, and augmented the cytotoxicity of 100 µM H2O2. Zn2+ is concluded to facilitate the toxicity of BZK. We suggest that the toxicity of BZK is determined after taking extracellular (plasma) and/or environmental Zn2+ levels into account.

Chlorhexidine possesses unique cytotoxic actions in rat thymic lymphocytes: Its relation with electrochemical property of membranes.

Chlorhexidine (CHX) is an antibacterial agent used in various types of pharmaceutical products. Therefore, CHX is easily found around us. Owing to its positive charge, the electrochemical property of cell membranes was assumed to be a key point of cytotoxic action of CHX. Depolarization of membranes attenuated the cytotoxic action of CHX in rat thymic lymphocytes. CHX interfered with annexin V binding to membranes. Manipulations to induce exposure of phosphatidylserine on the outer membrane surface augmented the cytotoxic action of CHX, indicating that changes in the electrochemical property of membranes affected the cytotoxic action of CHX. Hence, CHX might kill cells physiologically undergoing apoptosis, resulting instead in necrotic cell death. However, the threshold CHX concentration in this in vitro study was slightly higher than blood CHX concentrations observed clinically. Therefore, these results may support the safety of CHX use although CHX possesses unique cytotoxic actions described in this study.

Zinc increases vulnerability of rat thymic lymphocytes to arachidonic acid under in vitro conditions.

Previous studies on the cytotoxicity of arachidonic acid (ARA) elucidated the involvement of oxidative stress and Ca(2+). In the present study, the Zn(2+)-related cytotoxicity of ARA was studied by a flow cytometric technique with appropriate fluorescent probes in rat thymocytes. Addition of 10 µM ZnCl2 enhanced the increase in cell lethality induced by 10 µM ARA. The removal of Zn(2+) by Zn(2+) chelators attenuated the ARA-induced increase in cell lethality. Thus, Zn(2+) is suggested to be involved in ARA cytotoxicity. ARA at 3-10 µM elevated intracellular Zn(2+) level. The Zn(2+) chelators attenuated the ARA-induced increase in intracellular Zn(2+) level while ARA significantly increased intracellular Zn(2+) level in the presence of 3 µM ZnCl2, suggesting the involvement of external Zn(2+). Zn(2+) reportedly exerts cytotoxic action under oxidative stress induced by hydrogen peroxide, via an excessive increase in intracellular Zn(2+) levels. Since ARA induces oxidative stress, the simultaneous administration of zinc and ARA may be harmful.

Changes in cellular thiol content and intracellular Zn(2+) level by 1,4-naphthoquinone in rat thymocytes.

1,4-Naphthoquinone is an active metabolite of naphthalene and it is also found in diesel exhaust particles. It is known to cause oxidative stress. In this study, we characterized 1,4-naphthoquinone-mediated cytotoxicity and its effects on the levels of non-protein thiols and intracellular Zn(2+) in rat thymocytes (thymic lymphocytes) by using 5-chloromethylfluorescein (5-CMF) fluorescence and FluoZin-3 fluorescence, respectively. Low concentrations of 1,4-naphthoquinone (0.3µM) increased the intensity of 5-CMF fluorescence, which is used to measure non-protein thiols. In contrast, 5-CMF intensity decreased at higher concentrations (1-3µM) of 1,4-naphthoquinone. Removal of intracellular Zn(2+) attenuated the 1,4-naphthoquinone-induced augmentation of 5-CMF fluorescence. Additionally, 1,4-naphthoquinone (0.3-3µM) increased FluoZin-3 fluorescence, which is used to assess intracellular Zn(2+), in a concentration-dependent manner. The augmentation of FluoZin-3 fluorescence by 1,4-naphthoquinone was due to the release of intracellular Zn(2+), because the removal of extracellular Zn(2+) did not affect the augmentation of FluoZin-3 fluorescence. These results suggest that sublethal concentrations of 1,4-naphthoquinone (0.3-1µM) affect the cellular levels of non-protein thiols and intracellular Zn(2+). The difference in the observed decrease in cellular thiol content due to 1,4-naphthoquinone treatment and increase due to Zn(2+) release following 1,4-naphthoquinone treatment likely confers the change in cellular thiol content. Further, the increase in intracellular Zn(2+) concentration after 1,4-naphthoquinone exposure may change the activity of thymocytes because thymulin, a thymus-specific hormone, requires Zn(2+) for its biological activity.

Clioquinol-induced increase and decrease in the intracellular Zn2+ level in rat thymocytes.

AIMS: Clioquinol is emerging as a potential therapy for some diseases, such as Alzheimer disease and cancer. This agent is a lipophilic chelator of Zn(2+). In this study, the effect of clioquinol on the intracellular Zn(2+) level was examined in order to gain insights into the toxicological profile of clioquinol. MAIN METHODS: The effect of clioquinol was estimated using a flow cytometer and FluoZin-3, a fluorescent indicator for Zn(2+), in rat thymocytes. KEY FINDINGS: Clioquinol, at concentrations ranging from 10 to 300 nM, augmented FluoZin-3 fluorescence in a concentration-dependent manner. However, the effect induced by 1 µM clioquinol was less than that by 300 nM clioquinol. Removal of extracellular Zn(2+), using the membrane impermeable Zn(2+)-chelator diethylenetriamine-N,N,N',N″,N″-pentaacetic acid (DTPA), abolished the clioquinol-induced augmentation of FluoZin-3 fluorescence. Clioquinol did not augment Fluo-3 fluorescence, an indicator of intracellular Ca(2+), in the presence of DTPA. The results suggested that clioquinol caused an extracellular Zn(2+)-dependent increase in the intracellular Zn(2+) concentration. However, in the presence of DTPA, clioquinol at micromolar concentrations (1-10 µM) attenuated FluoZin-3 fluorescence in a concentration-dependent manner. Clioquinol even at 10 µM did not affect FluoZin-3 fluorescence under cell-free condition. The concentration-response relationship for the clioquinol induced change in Zn(2+) level appeared to be bell-shaped. These results indicate that micromolar concentrations of clioquinol, without chelated Zn(2+), decrease intracellular Zn(2+) concentration. SIGNIFICANCE: The effect of clioquinol on the intracellular Zn(2+) level varies, depending on the extracellular Zn(2+) concentration and the clioquinol concentration. Clioquinol may therefore exert various types of Zn(2+)-dependent cytotoxicity.

A comparison of the cellular actions of polaprezinc (zinc-L-carnosine) and ZnCl2.

AIMS: Zinc supplementation has been proven to be beneficial for the prevention of some health problems. Many zinc supplements are used for medical and nutritional purposes. However, it is difficult to distinguish between them in terms of their cellular actions. We compared the cellular actions of polaprezinc (zinc-l-carnosine) with those of ZnCl(2) in order to determine whether polaprezinc has greater zinc-related actions than ZnCl(2). MAIN METHODS: Cellular actions of polaprezinc and ZnCl(2) were estimated by flow-cytometric techniques with appropriate fluorescent probes in rat thymocytes. KEY FINDINGS: Both agents had almost equal stimulatory effects on the intracellular Zn(2+) level and cellular level of nonprotein thiol in a similar concentration-dependent manner. However, the increase in cell lethality caused by ZnCl(2) under severe oxidative stress was significantly greater than that caused by polaprezinc. SIGNIFICANCE: There are various zinc supplements, for example, zinc gluconate, zinc picolinate, and zinc methionine. However, the differences in their cellular actions have not been elucidated to date. Such studies could distinguish between zinc supplements.

Pharmacokinetics of ampicillin-sulbactam and the renal function-based optimization of dosing regimens for prophylaxis in patients undergoing cardiovascular surgery.

UNLABELLED: Surgical site infections are a major cause of postoperative morbidity and mortality in cardiovascular surgery. Proper antibiotic prophylaxis can reduce the rate of such infections, but the concentration of antibiotic must be maintained at an adequate level throughout the operation. This study aimed to use renal function to determine the most appropriate timing for intraoperative repeated dosing of ampicillin-sulbactam, a commonly used prophylactic antibiotic, to maintain adequate concentrations throughout the course of surgery. The mean volume of distribution, elimination rate constant, elimination half-life, and total clearance of ampicillin were 13.2 l, 0.652 h⁻¹, 1.32 h, and 8.45 l/h, respectively. A statistically significant (P < 0.0001) correlation (r = 0.771) was observed between the total clearance of ampicillin and creatinine clearance of the patients. Plasma concentrations of ampicillin were simulated with the pharmacokinetic parameters obtained. We developed a nomogram for adjusting the dosing interval according to renal function and predicted ampicillin trough concentrations. We revealed the best dosage and dosing interval for cardiovascular surgery by analyzing the perioperative pharmacokinetics of ampicillin-sulbactam administered prophylactically. We suggest that the dosage and dosing interval for ampicillin-sulbactam should be adjusted to optimize treatment efficacy and safety, on the basis of the MIC90 of methicillin-sensitive Staphylococcus aureus (MSSA) in each institution. TRIAL REGISTRATION: UMIN000007356.

Anti-microbial and therapeutic effects of modified Burow's solution on refractory otorrhea.

OBJECTIVE: Burow's solution, which contains 13% aluminum acetate, has been shown to be effective against chronic otitis media. Since the preparation of Burow's solution is time-consuming, its rapid preparation method has been recently developed. In this study, we evaluated the therapeutic effects of the modified Burow's solution on refractory otorrhea in patients with chronic suppurative otitis and its anti-microbial activity in vitro. METHODS: Fourteen ears of 12 patients with chronic otitis media, granular myringitis, otitis externa and postoperative mastoid cavity problems were treated topically with cotton swab/ball soaked with modified Burow's solution or its four-fold diluted ear drops once a week. We then examined the antimicrobial spectrum of modified Burow's solution against clinical bacterial isolates from otorrhea and laboratory bacterial strains in vitro. RESULTS: In all ears, refractory otorrhea disappeared after 1-17 weeks treatment of modified Burow's solution with a mean of 5.4 weeks without apparent side-effects such as ototoxicity. Modified Burow's solution inactivated all Gram positive bacteria within 5min except Enterococcus species, all Gram negative bacteria including Pseudomonas aeruginosa within 30s and Candida albicans within 2min. In addition, modified Burow's solution inactivated MRSA completely within 5min, while 80.6% of MRSA survived even a 20-min contact with 0.3% ofloxacin. CONCLUSION: These findings indicate that modified Burow's solution, in addition to bearing a broad antimicrobial activity, is as effective as the original Burow's solution in the treatment of chronic suppurative otitis.

Antihypertensive treatment using an angiotensin receptor blocker and a thiazide diuretic improves patients' quality of life: the Saga Challenge Antihypertensive Study (S-CATS).

The aim of the Saga Challenge Antihypertensive Study (S-CATS), a single-arm, prospective and multi-center trial, was to evaluate the effectiveness of combined antihypertensive treatment with losartan and hydrochlorothiazide (HCTZ). Enrolled in the study were a total of 161 patients with hypertension, who in spite of treatment with an angiotensin receptor blocker (ARB) alone or an ARB and calcium channel blocker (CCB), had not been able to reach blood pressure control goals set by the Japanese Society of Hypertension Guidelines (JSH 2004). The ARBs were replaced with a combination pill containing losartan (50 mg) and HCTZ (12.5 mg), and this treatment was continued for 3 months. This change in therapy resulted in significant decreases in systolic (158±14 to 137±15 mm Hg, P<0.001) and diastolic (85±11 to 76±10 mm Hg, P<0.001) blood pressure and heart rate (73±3 to 72±3) during the study. The patients' quality of life (QOL) score, the EuroQol 5 dimensions (EQ-5D) and the visual analog scale (VAS) (n=96; 70.0 (68.8-80.0) to 80.0 (70.0-90.0), P<0.01) all improved significantly. Another QOL score, the hypertension symptom score (HSS), which we originally developed for the S-CATS trial, decreased significantly (n=93; 4.0 (1.0-9.0) to 2.0 (1.0-8.0), P<0.05). The Pittsburgh sleep quality index (PSQI), which is a psychometric assessment of subjective sleep quality, also decreased significantly (n=45; 4.0 (2.0-7.0) to 3.0 (2.0-5.0), P<0.05). There was a significant correlation between a change in HSS (baseline value -3-months value) and a decrease in systolic blood pressure (n=93; R=0.241, P<0.05). These results suggest that an anti-hypertensive treatment combined with an ARB and a thiazide diuretic may improve patients' QOL, including sleep quality.

Putative role of intracellular Zn(2+) release during oxidative stress: a trigger to restore cellular thiol content that is decreased by oxidative stress.

Although the ability of zinc to retard the oxidative process has been recognized for many years, zinc itself has been reported to induce oxidative stress. In order to give some insights into elucidating the role of intracellular Zn(2+) in cells suffering from oxidative stress, the effects of N-ethylmaleimide (NEM) and ZnCl(2) on cellular thiol content and intracellular Zn(2+) concentration were studied by use of 5-chloromethylfluorescein diacetate (5-CMF-DA) and FluoZin-3 pentaacetoxymethyl ester (FluoZin-3-AM) in rat thymocytes. The treatment of cells with NEM attenuated 5-CMF fluorescence and augmented FluoZin-3 fluorescence in a dose-dependent manner. These NEM-induced phenomena were observed under external Zn(2+)-free conditions. Results suggest that NEM decreases cellular thiol content and induces intracellular Zn(2+) release. Micromolar ZnCl(2) dose-dependently augmented both FluoZin-3 and 5-CMF fluorescences, suggesting that the elevation of intracellular Zn(2+) concentration increases cellular thiol content. Taken together, it is hypothesized that intracellular Zn(2+) release during oxidative stress is a trigger to restore cellular thiol content that is decreased by oxidative stress.

Zinc at clinically-relevant concentrations potentiates the cytotoxicity of polysorbate 80, a non-ionic surfactant.

Polysorbate 80, a non-ionic surfactant, is used in the formula of water-insoluble anticancer agents for intravenous application. In our recent studies, this surfactant decreased cellular thiol content and the chemicals decreasing cellular thiol content increased intracellular Zn(2+) concentration. In this study using rat thymocytes, the effect of polysorbate 80 on FluoZin-3 fluorescence, an indicator for intracellular Zn(2+), and the influence of ZnCl(2) on cytotoxicity of polysorbate 80 were examined in order to test the possibility that Zn(2+) is involved in cytotoxic action of polysorbate 80. The surfactant at concentrations of 10 microg/ml or more significantly augmented FluoZin-3 fluorescent in a concentration-dependent manner, indicating an increase in intracellular Zn(2+) concentration. The increase by polysorbate 80 was also observed after removing extracellular Zn(2+), suggesting an intracellular Zn(2+) release. The simultaneous application of polysorbate 80 (30 microg/ml) and ZnCl(2) (10-30 microM) significantly increased cell lethality. The simultaneous application of ZnCl(2) accelerated the process of cell death induced by polysorbate 80 and the combination increased oxidative stress. Results may indicate that the cytotoxicity of polysorbate 80 at clinical concentrations is modified by micromolar zinc. Although there is no clinical report that polysorbate 80 and zinc salt are simultaneously applied to human as far as our knowledge, it may be speculated that zinc induces some diverse actions in cancer treatment with water-insoluble anticancer agent including nanoparticle drug of which the solvent is polysorbate 80.

Micromolar Zn(2+) potentiates the cytotoxic action of submicromolar econazole in rat thymocytes: possible disturbance of intracellular Ca(2+) and Zn(2+) homeostasis.

Econazole, one of imidazole antifungals, has been reported to exhibit an inhibitory action on Mycobacterium tuberculosis and its multidrug-resistant strains under in vitro and ex vivo conditions. There is a chemotherapeutic potential of econazole against tuberculosis. We have revealed that Zn(2+) at micromolar concentrations potentiates the cytotoxicity of imidazole antifungals by increasing membrane Zn(2+) permeability. It is reminiscent of a possibility that econazole exhibits harmful action on human in the presence of Zn(2+) at a physiological range when the agent is systemically administered. Because it is necessary to characterize the cytotoxic action of econazole in the presence of Zn(2+), we have cytometrically examined the effects of econazole, ZnCl(2), and their combination on rat thymocytes. ZnCl(2) at concentrations ranging from 1 microM to 30 microM significantly increased the lethality induced by 10 microM econazole in a concentration-dependent manner. Econazole at a sublethal concentration of 1 microM significantly augmented the intensity of side scatter in the presence of micromolar ZnCl(2), suggesting the change in an intracellular circumstance by the combination of econazole and ZnCl(2). Econazole at 0.3 microM or more in the presence of ZnCl(2) increased the intensity of Fluo-3 fluorescence, an indicator for intracellular Ca(2+). Furthermore, the intensity of FluoZin-3 fluorescence, an indicator for intracellular Zn(2+), was also augmented by econazole at 0.1 microM or more in the presence of ZnCl(2). Results suggest that the combination of submicromolar econazole with micromolar ZnCl(2) may increase the intracellular concentration of Ca(2+) and Zn(2+), leading to disturbance of intracellular Ca(2+) and Zn(2+) homeostasis that triggers cytotoxic action.

Zn(2+), derived from cell preparation, partly attenuates Ca(2+)-dependent cell death induced by A23187, calcium ionophore, in rat thymocytes.

A23187, a calcium ionophore, is used to induce Ca(2+)-dependent cell death by increasing intracellular Ca(2+) concentration ([Ca(2+)](i)) under in vitro condition. Since this ionophore also increases membrane permeability of metal divalent cations such as Zn(2+) and Fe(2+) rather than Ca(2+), trace metal cations in cell suspension may affect Ca(2+)-dependent cell death induced by A23187. Therefore, the effects of chelators for divalent metal cations, EDTA and TPEN, on the A23187-induced cytotoxicity were cytometrically examined in rat thymocytes. The cytotoxicity of A23187 was attenuated by 1mM EDTA while it was augmented by 50 microM EDTA and 10 microM TPEN. These changes were statistically significant. The A23187-induced increase in Fluo-3 fluorescence intensity, a parameter for [Ca(2+)](i), was significantly reduced by 1mM EDTA while it was not the case for 50 microM EDTA and 10 microM TPEN. The intensity of FluoZin-3 fluorescence, a parameter for [Zn(2+)](i), increased by A23187 was respectively reduced by 50 microM EDTA and 10 microM TPEN. It is suggested that the attenuation of A23187-induced cytotoxicity by 1mM EDTA is due to the chelation of extracellular Ca(2+) and Zn(2+) while the augmentation by 50 microM ETDA or 10 microM TPEN is due to the chelation of extracellular Zn(2+). The Tyrode's solution without thymocytes contained 32.4 nM of zinc while it was 216.9 nM in the cell suspension. In conclusion, trace Zn(2+), derived from cell preparation, partly attenuates the Ca(2+)-dependent cell death induced by A23187.

Antimicrobial effects of drugs against multidrug-resistant Pseudomonas aeruginosa.

We evaluated the effects of antimicrobial drugs on four strains of Pseudomonas aeruginosa that are resistant to eight widely used antipseudomonal drugs (piperacillin, piperacillin-tazobactam, imipenem, meropenem, ceftazidime, aztreonam, amikacin, ciprofloxacin) and colistin. In the killing test, colistin (2 microg/ml) was the most effective, followed by aztreonam (48 microg/ml), piperacillin-tazobactam (192-4 microg/ml), piperacillin (192 microg/ml), and a three drug combination of azetreonam (16 microg/ml), ceftazidime (16 microg/ml), and amikacin (4 microg/ml). Six hours after drug addition, colistin (2 microg/ml), aztreonam (48 microg/ml), piperacillin-tazobactam (192-4 microg/ml), piperacillin (192 microg/ml), and the above three drug combination had bacteriostatic effects on all four strains. Colistin, three time breakpoint of aztreonam, piperacillin, or piperacillin-tazobactam, and the three drug combination of aztreonam, ceftazidime, and amikacin were effective in vitro.

Imidazole antifungals, but not triazole antifungals, increase membrane Zn2+ permeability in rat thymocytes Possible contribution to their cytotoxicity.

The use of zinc as a nutritional supplement has become common in many countries. Since zinc has diverse actions, it may be difficult to predict its synergistic and/or antagonistic action in simultaneous presence of drug(s). The combination of imidazole antifungals, but not triazole antifungals, with 3-30 microM ZnCl2 significantly increased the lethality of rat thymocytes. Since intracellular Zn2+ exerts various actions on the process of cell death, there is a possibility that imidazole antifungals, but not triazole antifungals, increases concentration of intracellular Zn2+ ([Zn2+]i). To test the possibility, we examined the effects of imidazole and triazole antifungals on [Zn2+]i of rat thymocytes in absence and presence of extracellular Zn2+ by the use of FluoZin-3, a fluorescent Zn2+ indicator. Imidazole antifungals (clotrimazole, econazole, and oxiconazole) increased the [Zn2+]i in the presence of extracellular Zn2+ while it was not the case for triazole antifungals (itraconazole and fluoconazole). Thus, it is suggested that imidazole antifungals increase the membrane permeability of Zn2+. The potency order in the augmentation of FluoZin-3 fluorescence by imidazole antifungals in the presence of extracellular Zn2+ was the same as that in their cytotoxic action. Therefore, the cytotoxic action of imidazole antifungals may be related to their action on membrane Zn2+ permeability.

Synergic cytotoxic action induced by simultaneous application of zinc and clotrimazole in rat thymocytes.

In our previous study, the application of clotrimazole, an antifungal drug, with CdCl(2) or PbCl(2) significantly increased cell lethality of rat thymocytes, even though their individual concentrations were ineffective in affecting the viability. This observation prompted us to study the case for the combination of clotrimazole and ZnCl(2) because the use of zinc as a nutritional supplement has become common. Their combination induced very potent cytotoxic action on rat thymocytes with "bell-shape" dose-response relation. An acceleration of apoptotic process by the combination was suggested for the mechanism. The present result may provide a new insight into toxicological characteristics of clotrimazole.

Duration of postictal psychotic episodes.

PURPOSE: To clarify duration of postictal psychosis (PIP) episodes and identify factors that influence its duration. METHODS: Fifty-eight patients with epilepsy exhibited 151 PIP episodes during a mean follow-up period of 12.8 years. Distribution of the duration of these episodes was determined, and factors potentially affecting were analyzed. Factors analyzed included PIP-related variables (i.e., antecedent seizures and the lucid interval) and patient characteristics (i.e., type of epilepsy, lateralization of EEG abnormalities, and intellectual functioning). RESULTS: The mean duration of the 58 first PIP episodes was 10.5 days, and that of all 151 PIP episodes (including multiple episodes) was 9.2 days. Approximately 95% of the PIP episodes resolved within 1 month. Most PIP-related variables, except for antipsychotic drugs administered, were not associated with duration of the episodes. Several patient characteristics, i.e., history of interictal psychosis, family history of psychosis, and intellectual functioning, were associated with duration of the PIP episodes. CONCLUSIONS: This study showed that most PIP episodes last less than 1 month. PIP episodes appear to be prolonged when individuals have an underlying vulnerability to psychosis. Clinical phenomena that can trigger PIP may not determine the course of the PIP episode.