References on the Administration of Antipsychotic Agents Using ALZET® Osmotic Pumps

1. Chlorpromazine

2808 Konings, P.N.M., Culling-Berglund, A., Davis, T.P. Chronic haloperidol and chlorpromazine treatment alters in vitro B-endorphin metabolism in rat brain. Eur. J. Pharmacol 1990; 191(--):115-128. >>> Haloperidol; Chlorpromazine; Saline, sterile; SC; rat; 2001; 2ML1; controls received mp w/ vehicle.

1348 Myschuk, T.N., Sawich, C.L., Allen, G. Long term (1 week) tranquilization of mice using Alzet(R) mini-osmotic pumps. Can. Lab Anim. Sci. News 1987; 20(-1-):18-20. >>> Chlorpromazine HCl; IP; SC; mice; 2002; complications with sc delivery; no stress/stress.

15393 Davis, T.P., Culling-Berglund, A. Neuroleptic drug treatment alters in vitro central neurotensin metabolism. Psychoneuroendocrinology 1987; 12(-4-):253-260. >>> Chlorpromazine; Haloperidol; SC; rat; 2001; 2ML1; controls received sham op; concomitant infusion of agents; comparison of agents effects; functionality of mp verified by gravimetric analyses.

908 Frey, P. Changes in cholecystokinin content in rat brain after subchronic treatment with neuroleptics. Ann. N. Y. Acad. Sci 1985; 448(--):601-603. >>> Flupenthixol, cis-; Flupenthixol, trans-; Amitriptyline; Amphetamine; Atropine; Chlorpromazine; Clozapine; Fluphenazine; Haloperidol; Morphine; Prazosin; SC; rat; mp model not stated; comparison of sc injections vs. mp infusion; antihypertensive.

447 Davis, T.P., Schoemaker, H., Culling, A.J. Centrally acting drugs alter in vitro B-endorphin processing in the rat. Eur. J. Pharmacol 1984; 100(--):249-251. >>> Chlorpromazine; haloperidol; phenobarbital; promethazine; SC; Rat; 2001; Comparison of agents effects.

385 Frey, P. Cholecystokinin octapeptide levels in rat brain are changed after subchronic neuroleptic treatment. Eur. J. Pharmacol 1983; 95(--):87-92. >>> Chlorpromazine; Clozapine; Haloperidol; HCl; Saline; SC; rat; 2ML2; 2ML4; comparison of single injec vs. infusion; comparison of agents effects; Hal. given for 2&4 weeks, Chlor.&Cloz. for 2 weeks; saline&HCl vehicle used w/Cloz., others used saline only; stability of Hal., Chlor.&Cloz. by TLC.

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2. Clozapine

14662 Anderson, P.M., Pinault, D., O'Brien, T.J., Jones, N.C., Jones, N.C. Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical gamma oscillations. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 2014; 17(--):1895-1904. >>> Haloperidol; clozapine; LY379268; Saline; acetic acid; water, sterile; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Wistar, 10-12 weeks old, 250-350g); functionality of mp verified by residual volume; behavioral testing (locomotor activity); LY379268 is a metabotropic glutamate 2/3 receptor agonist (mGluR 2/3);.

12086 Steward, L.J., Kennedy, M.D., Morris, B.J., Pratt, J.A. Chronic phencyclidine (PCP)-induced modulation of muscarinic receptor mRNAs in rat brain : Impact of antipsychotic drug treatment. Neuropharmacology 2012; 62(-3-):1554-1563. >>> Clozapine; haloperidol; Acetic acid; saline; water; SC; Rat; 2ML4; Animal info (Hooded Long Evans, 186-248 g); pump functionailty verified via residual volume.

12085 Amitai, N., Kuczenski, R., Behrens, M.M., Markou, A. Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats. Neuropharmacology 2012; 62(-3-):1422-1431. >>> Clozapine; HCl; saline; SC; Rat; 2ML1; Controls received mp w/ vehicle; animal info (Wistar, male, 300 g); pumps replaced after 7 days;"The limited solubility of clozapine at the concentration that was required to deliver 4 mg/kg/day in the maximal volume that could be contained in the minipumps prevented the use of a single 14 day osmotic minipump; thus, two successive 7 day minipumps were used"pg 1423; wound clips used; post op. care (antibacterial ointment) pg 1423.

10915 Thomson, D.M., Mcvie, A., Morris, B.J., Pratt, J.A. Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine. Psychopharmacology 2011; 213(-4-):681-695. >>> Clozapine; Acetic acid, glacial; water, sterile; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, hooded, Long-Evans, 333 g).

9716 Amitai, N., Semenova, S., Markou, A. Clozapine attenuates disruptions in response inhibition and task efficiency induced by repeated phencyclidine administration in the intracranial self-stimulation procedure. European Journal of Pharmacology 2009; 602(-1-):78-84. >>> Clozapine; Hydrochloric acid; saline; SC; Rat; 2ML1; Controls received mp w/ vehicle; pumps replaced after 7 days; post op. care (antibacterial ointment on incision area); animal info (Wistar rats, 300 g.); antipsychotic; subsequent pump implanted contralateral to the first minipump.

9105 Abrams, D.J., Zheng, L., Choo, K.S., Yang, J.J., Wei, W., Anchordoquy, T.J., Zawia, N.H., Stevens, K.E. An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients. SCHIZOPHRENIA RESEARCH 1999; 112(-1091-):86-96. >>> Clozapine; Cyclodextrin, hydroxypropyl, beta; CSF/CNS; Rat; Controls received mp w/ saline; ALZET brain infusion kit used; animal info (male, Sprague Dawley, 250-300g.); Schizophrenia.

6916 Semenova, S., Markou, A. Clozapine treatment attenuated somatic and affective signs of nicotine and amphetamine withdrawal in subsets of rats exhibiting hyposensitivity to the initial effects of clozapine. Biological Psychiatry 2003; 54(-11-):1249-1264. >>> Nicotine tartrate; amphetamine; clozapine; HCL; saline; SC; Rat; 2ML1; Controls received mp w/ vehicle; pumps replaced every 7 days for the 14 day study infusing clozapine; dependence;"in this experiment involving three pump implantations each pump was placed in a different part of the rats'body (left or right side of the back of the animal or at the shoulder area)."p. 1252; behavioral study.

6362 Cochran, S.M., Kennedy, M., McKerchar, C.E., Steward, L.J., Pratt, J.A., Morris, B.J. Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: Differential modulation by antipsychotic drugs. Neuropsychopharmacology 2003; 28(-2-):265-275. >>> Clozapine; haloperidol; Acetic acid, glacial; water; SC; Rat; 2ML4; Controls received mp w/ vehicle.

6329 Kapur, S, Susan C. Antipsychotic Dosing in Preclinical Models is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy. Journal of Pharmacology and Experimental Therapeutics 2003; 305(-2-):625-631. >>> Haloperidol; olanzapine; risperidone; quetiapine; clozapine; Water; acetic acid, glacial; SC; Rat; 2ML2; Plasma levels taken; dose-response (p. 629); comparison of daily injections vs. chronic mp; half-life (p. 626) 2-4 hours; haloperidol and risperidone were dissolved in distilled water; olanzapine, quetiapine and clozapine were dissolved in 1% to 2% acetic acid; great dose information;"we propose that only administration by pump (or administration more than four times a day[injections]) can provide clinical-like occupancies for haloperidol, olanzapine, and risperidone."p. 630.

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3. Fluphenazine

908 Frey, P. Changes in cholecystokinin content in rat brain after subchronic treatment with neuroleptics. Ann. N. Y. Acad. Sci 1985; 448(--):601-603. >>> Flupenthixol, cis-; Flupenthixol, trans-; Amitriptyline; Amphetamine; Atropine; Chlorpromazine; Clozapine; Fluphenazine; Haloperidol; Morphine; Prazosin; SC; rat; mp model not stated; comparison of sc injections vs. mp infusion; antihypertensive.

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4. Haloperidol

16217 Oda, Y., Tadokoro, S., Takase, M., Kanahara, N., Watanabe, H., Shirayama, Y., Hashimoto, K., Iyo, M. G protein-coupled receptor kinase 6/beta-arrestin 2 system in a rat model of dopamine supersensitivity psychosis. J Psychopharmacol 2015; 29(-12-):1308-13. >>> Haloperidol; Acetic acid, glacial; water; SC; rat; 2ML2; Controls received mp w/ vehicle; animal info (Eleven-week-old male Wistar rats, 240–260 g ); functionality of mp verified by ELIZA testing; 2% acetic acid used; good methods (pg 1309); stress/adverse reaction: “One animal did not recover from pump-implanting surgery and was excluded from analysis” (see pg. 1310); behavioral testing (MAP-induced locomotion test); Vehicle pH adjusted to 3.6-3.8 with NaOH; 9mm wound clips used; Dose (0.75 mg/kg/d;);.

16116 El Hage, C., Bedard, A. M., Samaha, A. N. Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function. Neuropharmacology 2015; 99(--):715-25. >>> Haloperidol; Olanzapine; Acetic acid; water; SC; rat; 2ML2; Controls received sham surgery; animal info: Male Sprague-Dawley rats; %0.5 or %2 of acetic acid; behavioral testing (trained to associate the delivery of 100 ml water (the unconditioned stimulus; UCS) into a receptacle with a light/tone conditioned stimulus (CS)); Dose: 0.5 mg/kg/day (haloperidol); 10 mg/kg/day (olanzapine).

16105 Charron, A., Hage, C. E., Servonnet, A., Samaha, A. N. 5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity. Eur Neuropsychopharmacol 2015; 25(-12-):2381-93. >>> Haloperidol; Acetic acid, glacial; water; SC; rat; 2ML2; Controls received sham surgery consisting of an incision and sutures; animal info: Male Sprague-Dawley rats 200–225g; water (pH 5) used; half-life (p. 2383 ), 1.5 hours; models the kinetics of standard antipsychotic treatment in patients; Dose: 0.5 mg/ kg/day.

16002 Madularu, D., Kulkarni, P., Ferris, C. F., Brake, W. G. Changes in brain volume in response to estradiol levels, amphetamine sensitization and haloperidol treatment in awake female rats. Brain Res 2015; 1618(--):100-10. >>> Haloperidol; SC; Rat; 2002; Controls received sham surgery; animal info (female, Sprague Dawley, 200-250g 2-3 months old, OVX); post op. care (Anafen 0.1 mL/rat; antibiotic ointment); MRI; PEEK; Dose (0.25 mg/kg/day);.

14740 Gao, J., Li, M., Li, M. Differential effects of intermittent versus continuous haloperidol treatment throughout adolescence on haloperidol sensitization and social behavior in adulthood. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY&BIOLOGICAL PSYCHIATRY 2014; 54(--):67-75. >>> Haloperidol; Water, sterile; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Sprague Dawley, PND44-71); comparison of injection vs mp; post op. care (incision cleaned with 75% ethanol); behavioral testing (two-way avoidance conditioning apparatus; locomotor activity monitoring apparatus; avoidance training); dependence; used 9mm wound clips; pumps wiped with 75% ethanol; pumps removed after 28 days;.

14662 Anderson, P.M., Pinault, D., O'Brien, T.J., Jones, N.C., Jones, N.C. Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical gamma oscillations. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY 2014; 17(--):1895-1904. >>> Haloperidol; clozapine; LY379268; Saline; acetic acid; water, sterile; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Wistar, 10-12 weeks old, 250-350g); functionality of mp verified by residual volume; behavioral testing (locomotor activity); LY379268 is a metabotropic glutamate 2/3 receptor agonist (mGluR 2/3);.

13880 Natesan, S., Ashworth, S., Nielsen, J., Tang, S.P., Salinas, C., Kealey, S., Lauridsen, J.B., Stensbol, T.B., Gunn, R.N., Rabiner, E.A., Kapur, S., Kapur, S. Effect of chronic antipsychotic treatment on striatal phosphodiesterase 10A levels: a [(11C)]MP-10 PET rodent imaging study with ex vivo confirmation. TRANSLATIONAL PSYCHIATRY 2014; 4(--):U4-U10. >>> Haloperidol; Cyclodextrin, B-hydroxypropyl-; ascorbic acid; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Sprague Dalwy, 308-456g); functionality of mp verified by plasma; 20% B-hydroxypropylcyclodextrin used; behavioral testing (chewing movements);"Daily intraperitoneal injections in rodents lead to plasma levels that dip to a negligible level during a 24-h period as most antipsychotics have a half-life of 2-4 h in rodents, whereas the half-life of most antipsychotics in humans is usually 12-24 h.14 Hence, the present study was designed taking into consideration a delivery method (subcutaneous mini-osmotic pumps) that maintained constant plasma levels to evaluate the effect of chronic antipsychotic treatment on striatal PDE10A levels in rodents"pg 1;.

13606 Madularu, D., Shams, W.M., Brake, W.G. Estrogen potentiates the behavioral and nucleus accumbens dopamine response to continuous haloperidol treatment in female rats. European Journal of Neuroscience 2014; 39(-2-):257-265. >>> Haloperidol; Saline; SC; Rat; 2002; Animal info (female, Sprague Dawley, ovariectomized); behavioral testing (motor activity); replacement therapy (ovariectomized); pump removed after 12 days;.

13590 Cazorla, M., de Carvalho, F.D., Chohan, M.O., Shegda, M., Chuhma, N., Rayport, S., Ahmari, S.E., Moore, H., Kellendonk, C. Dopamine D2 Receptors Regulate the Anatomical and Functional Balance of Basal Ganglia Circuitry. Neuron 2014; 81(-1-):153-164. >>> Haloperidol; Lactic acid; sodium hydroxide; SC; Mice (transgenic); 2002; Controls received mp w/ vehicle; animal info (male, D2R-OE, adult); behavioral testing (open field, locomotor activity);.

13177 Bedard, A.M., Maheux, J., Levesque, D., Samaha, A.N. Prior Haloperidol, but not Olanzapine, Exposure Augments the Pursuit of Reward Cues: Implications for Substance Abuse in Schizophrenia. SCHIZOPHRENIA BULLETIN 2013; 39(-3-):692-702. >>> Haloperidol; olanzapine; Acetic acid; water, distilled; SC; Rat; 2ML2; Animal info (male, sprague-dawley, 200-225g); half-life (24hr, haloperidol); behavioral testing (lever pressing).

13003 Tadokoro, S., Okamura, N., Sekine, Y., Kanahara, N., Hashimoto, K., Iyo, M. Chronic Treatment With Aripiprazole Prevents Development of Dopamine Supersensitivity and Potentially Supersensitivity Psychosis. SCHIZOPHRENIA BULLETIN 2012; 38(-5-):1012-1020. >>> Haloperidol; ariprprazole; Acetic acid, glacial; water; SC; Rat; 2ML2; Control animals received mp w/ vehicle; animal info (Sprague Dawley, male, 240-260 g); wound clips used; pumps replaced after 14 days; good methods"When a subsequent pump was implanted in exchange for a former one, the most recent pump was inserted on the other side of the scapulae across from the former pump."pg 1013.

12964 Mondelli, V., Anacker, C., Vernon, A.C., Cattaneo, A., Natesan, S., Modo, M., Dazzan, P., Kapur, S., Pariante, C.M. Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways. TRANSLATIONAL PSYCHIATRY 2013; 3(-;-):U25-U31. >>> Haloperidol; olanzapine; SC; Rat; 2ML4; Control animals received mp w/ vehicle; animal info (Sprague Dawley, male, 9 wks old, 240-250 g); pumps replaced after 28 days; long-term study.

12340 Vernon, A.C., Natesan, S., Crum, W.R., Cooper, J.D., Modo, M., Williams, S.C.R., Kapur, S. Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation. Biological Psychiatry 2012; 71(-10-):855-863. >>> Haloperidol; Cyclodextrin, hydroxypropyl beta; ascorbic acid; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (Sprague Dawley, male, 10 wks old); MRI; 20% cyclodextrin used; long-term study; functionality of mp verified via plasma drug levels.

12086 Steward, L.J., Kennedy, M.D., Morris, B.J., Pratt, J.A. Chronic phencyclidine (PCP)-induced modulation of muscarinic receptor mRNAs in rat brain : Impact of antipsychotic drug treatment. Neuropharmacology 2012; 62(-3-):1554-1563. >>> Clozapine; haloperidol; Acetic acid; saline; water; SC; Rat; 2ML4; Animal info (Hooded Long Evans, 186-248 g); pump functionailty verified via residual volume.

11649 Vernon, A.C., Natesan, S., Modo, M., Kapur, S. Effect of Chronic Antipsychotic Treatment on Brain Structure: A Serial Magnetic Resonance Imaging Study with Ex Vivo and Postmortem Confirmation. Biological Psychiatry 2011; 69(-10-):936-944. >>> Haloperidol; olanzapine; Cyclodextrin, beta-hydroxypropyl; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Sprague Dawley, 240-250 g, 9 wks old); pumps replaced after 28 days; half-life 2.5 hours (p. 937);"MRI-safe"pumps; 20% cyclodextrin used; long-term study.

11614 Simpson, E.H., Kellendonk, C., Ward, R.D., Richards, V., Lipatova, O., Fairhurst, S., Kandel, E.R., Balsam, P.D. Pharmacologic Rescue of Motivational Deficit in an Animal Model of the Negative Symptoms of Schizophrenia. Biological Psychiatry 2011; 69(-10-):928-935. >>> Haloperidol; Saline; SC; Mice; 2004; Controls received mp w/ vehicle; animal info (D2R-OE).

11153 Bedard, A.M., Maheux, J., Levesque, D., Samaha, A.N. Continuous, but not Intermittent, Antipsychotic Drug Delivery Intensifies the Pursuit of Reward Cues. Neuropsychopharmacology 2011; 36(-6-):1248-1259. >>> Haloperidol; Acetic acid, glacial; water; SC; Rat; 2ML2; Controls received mp w/ vehicle; animal info (male, Sprague-Dawley, 200-225 g); comparison of injections vs mp.

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5. Olanzapine

16116 El Hage, C., Bedard, A. M., Samaha, A. N. Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function. Neuropharmacology 2015; 99(--):715-25. >>> Haloperidol; Olanzapine; Acetic acid; water; SC; rat; 2ML2; Controls received sham surgery; animal info: Male Sprague-Dawley rats; %0.5 or %2 of acetic acid; behavioral testing (trained to associate the delivery of 100 ml water (the unconditioned stimulus; UCS) into a receptacle with a light/tone conditioned stimulus (CS)); Dose: 0.5 mg/kg/day (haloperidol); 10 mg/kg/day (olanzapine).

13261 Schmidt, R.H., Jokinen, J.D., Massey, V.L., Falkner, K.C., Shi, X., Yin, X.M., Zhang, X., Beier, J.I., Arteel, G.E. Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs. Journal of Pharmacology and Experimental Therapeutics 2013; 347(-1-):126-135. >>> Olanzapine; Saline; SC; Mice; Animal info (female, C57BI/6J, 8 wks old); functionality of mp verified by (oral glucose test); pumps replaced every (2 weeks); post op care (anesthesized with ketamine/xylazine (100/15 mg/kg/ip); antipsychotic.

13177 Bedard, A.M., Maheux, J., Levesque, D., Samaha, A.N. Prior Haloperidol, but not Olanzapine, Exposure Augments the Pursuit of Reward Cues: Implications for Substance Abuse in Schizophrenia. SCHIZOPHRENIA BULLETIN 2013; 39(-3-):692-702. >>> Haloperidol; olanzapine; Acetic acid; water, distilled; SC; Rat; 2ML2; Animal info (male, sprague-dawley, 200-225g); half-life (24hr, haloperidol); behavioral testing (lever pressing).

12964 Mondelli, V., Anacker, C., Vernon, A.C., Cattaneo, A., Natesan, S., Modo, M., Dazzan, P., Kapur, S., Pariante, C.M. Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways. TRANSLATIONAL PSYCHIATRY 2013; 3(-;-):U25-U31. >>> Haloperidol; olanzapine; SC; Rat; 2ML4; Control animals received mp w/ vehicle; animal info (Sprague Dawley, male, 9 wks old, 240-250 g); pumps replaced after 28 days; long-term study.

12246 Remington, G., Mann, S., McCormick, P., Nobrega, J.N., Hahn, M., Natesan, S. Modeling chronic olanzapine exposure using Pharmacological limitations. Pharmacology Biochemistry and Behavior 2011; 100(-1-):86-89. >>> Olanzapine; Acetic acid, glacial; water, sterile; In vitro; 2ML4; Controls received vehicle; drug levels verified using a liquid-liquid extraction and liquid chromatography;"We suggest that olanzapine administration via (ALZET pumps) represents a viable option for (sub)chronic exposure with the caveats that a) duration be confined to 2 weeks..., and b) consideration be given to strategies in dissolving olanzapine that diminish the risk of oxidation."pg 89;"we strongly agree with van der Zwaal and colleagues (2008) that the issue of drug degradation is not specific to olanzapine, and that it is imperative to establish whether compounds being considered for minipump administration are capable of remaining stable in solution at body temperature.".

11649 Vernon, A.C., Natesan, S., Modo, M., Kapur, S. Effect of Chronic Antipsychotic Treatment on Brain Structure: A Serial Magnetic Resonance Imaging Study with Ex Vivo and Postmortem Confirmation. Biological Psychiatry 2011; 69(-10-):936-944. >>> Haloperidol; olanzapine; Cyclodextrin, beta-hydroxypropyl; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Sprague Dawley, 240-250 g, 9 wks old); pumps replaced after 28 days; half-life 2.5 hours (p. 937);"MRI-safe"pumps; 20% cyclodextrin used; long-term study.

10880 Coccurello, R., Brina, D., Caprioli, A., Conti, R., Ghirardi, O., Schepis, F., Moles, A. 30 Days of Continuous Olanzapine Infusion Determines Energy Imbalance, Glucose Intolerance, Insulin Resistance, and Dyslipidemia in Mice. Journal of Clinical Psychopharmacology 2009; 29(-6-):576-583. >>> Olanzapine; Acetic acid; saline, isotonic; sodium hydroxide; SC; Mice; 2004; Controls received mp w/ vehicle; animal info (CD-1, 11 wks old, female); functionality of mp verified by residual volume;"Although (degradation of AAP agents in mini-pump reservoir over time) is a serious concern, significant increases of body weight and food intake were found in female rats33Y35 and mice14 under constant OL infusion via implanted mini-pumps"pg 582.

10105 Joosen, M.J.A., Jousma, E., van den Boom, T.M., Kuijpers, W.C., Smit, A.B., Lucassen, P.J., Van Helden, H.P.M. Long-term cognitive deficits accompanied by reduced neurogenesis after soman poisoning. Neurotoxicology 2009; 30(-1-):72-80. >>> Olanzapine; Acetic acid, glacial; SC; Rat; 2ML4; Functionality of mp verified by residual volume; animal info (male, Sprague Dawley); stability verified for 4 weeks by electrospray MS/MS.

9915 van der Zwaal, E.M., Luijendijk, M.C.M., Adan, R.A.H., la Fleur, S.E. Olanzapine-induced weight gain: Chronic infusion using osmotic minipumps does not result in stable plasma levels due to degradation of olanzapine in solution. European Journal of Pharmacology 2008; 585(-1-):130-136. >>> Olanzapine; Acetic acid, glacial; saline; hydrochloric acid; water, distilled; SC; Rat; 2ML4; Controls received mp w/vehicle; comparison of SC injections vs. mp; half-life (p.130)"2-5 h in rats"; animal info (male, Wistar);"...at the end of the study, we noticed a strong discoloration of the solution remaining in the minipumps of the olanzapine-treated rats (from bright orange to dark green), as well as a dark precipitate in the pumps interior, which was most notable in the highest dose group"pg 132;"...this suggests that lower plasma levels of olanzapine occur over time only when osmotic minipumps are used and not with daily s.c. injections."pg 135;"Only drugs that are (relatively) stable in a solution at body temperature will result in truly constant drug delivery from an osmotic minipump and, therefore, enable accurate and reliable experimental results."pg 136.

9669 Lykkegaard, K., Larsen, P.J., Vrang, N., Bock, C., Bock, T., Knudsen, L.B. The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance. SCHIZOPHRENIA RESEARCH 2008; 103(-1-3-):94-103. >>> Olanzapine; PBS; NaOH; lactic acid; SC; Rat; 2ML4; Controls received mp w/ vehicle; stress/adverse reaction: (see pg. 96) 6 animals out of 40 developed local irritation/wounds at implantation site; post op. care (carprofen); animal info (male, Sprague Dawley, 240 g.);"we used continuous subcutaneous administration of olanzapine via osmotic minipumps in order to obtain a steady-state of olanzapine with no sedation. The result of this... is an animal model that mimics the side effect profile encountered in schizophrenic patients treated with olanzapine. This may be a valuable, rapid, and inexpensive model for screening."(p. 100).

9637 Chintoh, A.F., Mann, S.W., Lam, T.K.T., Giacca, A., Remington, G. Insulin resistance following continuous, chronic olanzapine treatment: An animal model. SCHIZOPHRENIA RESEARCH 2008; 104(-1-3-):23-30. >>> Olanzapine; Acetic acid; SC; Rat; 2ML4; Controls received no treatment; dose-response (fig. 2); animal info (male, Sprague Dawley, 225-275 g.);"The choice of administration by osmotic pump acknowledged the rapid metabolism of antipsychotics reported in rodents... and an effort to more closely approximate the human condition by providing sustained exposure."(p. 24); behavioral testing (locomotor activity).

9514 Wallingford, N.M., Sinnayah, P., Bymaster, F.P., Gadde, K.M., Krishnan, R.K., McKinney, A.A., Landbloom, R.P., Tollefson, G.D., Cowley, M.A. Zonisamide prevents olanzapine-associated hyperphagia, weight gain, and elevated blood glucose in rats. Neuropsychopharmacology 2008; 33(-12-):2922-2933. >>> Olanzapine; Lactic acid; SC; Rat; 2ML2; Controls received mp w/ vehicle; comparison of SC injections vs. mp; no stress (see pg. 2923); animal info (female, Sprague Dawley, 230-275 g.);"Mini-pumps were used to chronically deliver OLZ in order to minimize stress-related changes in food intake and body weight associated with daily handling and intraperitoneal (IP) injection."(p. 2923).

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6. Quetiapine

16030 Ito, N., Ito, K., Koshimichi, H., Hisaka, A., Honma, M., Igarashi, T., Suzuki, H. Contribution of protein binding, lipid partitioning, and asymmetrical transport to drug transfer into milk in mouse versus human. Pharm Res 2013; 30(-9-):2410-22. >>> acetaminophen, cephalothin sodium salt, clindamycin hydrochloride, disopyramide phosphate salt, labetalol hydrochloride, nitrofurantoin +-propranolol hydrochloride, terbutaline hemisulfate salt, verapamil hydrochloride, Acyclovir, alprazolam, atenolol, anhydrous caffeine, cefotaxime sodium salt, cephapirin sodium salt, diltiazem hydrochloride, metronidazole, nitrazepam, prednisolone, 6-propyl-2-thiouracil, trazadone hydrochloride, chloramphenicol, cimetidine, theophylline, fluconazole, metoprolol, mirtazapine, praziquantel, quetiapine fumarate, triprolidine hydrochloride, metformin, moclobemide.; DMSO; water; IP; mice; 1003D; animal info: lactating mice, postnatal age of 14 days; functionality of mp verified by measurement of drug concentration in milk and plasma; mp were used to infuse study lactational drug transfer..

6329 Kapur, S, Susan C. Antipsychotic Dosing in Preclinical Models is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy. Journal of Pharmacology and Experimental Therapeutics 2003; 305(-2-):625-631. >>> Haloperidol; olanzapine; risperidone; quetiapine; clozapine; Water; acetic acid, glacial; SC; Rat; 2ML2; Plasma levels taken; dose-response (p. 629); comparison of daily injections vs. chronic mp; half-life (p. 626) 2-4 hours; haloperidol and risperidone were dissolved in distilled water; olanzapine, quetiapine and clozapine were dissolved in 1% to 2% acetic acid; great dose information;"we propose that only administration by pump (or administration more than four times a day[injections]) can provide clinical-like occupancies for haloperidol, olanzapine, and risperidone."p. 630.

6072 Tarazi, F.I., Baldessarini, R.J., Kula, N.S., Zhang, K.H. Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: Implications for antipsychotic drug treatment. Journal of Pharmacology and Experimental Therapeutics 2003; 306(-3-):1145-1151. >>> Olanzapine; risperidone; quetiapine fumerate; SC; Rat; Functionality of mp verified by residual volume; antipsychotic drugs.

6027 Tarazi, F.I., Zhang, K.H., Baldessarini, R.J. Long-term effects of newer antipsychotic drugs on neuronal nitric oxide synthase in rat brain. NITRIC OXIDE-BIOLOGY AND CHEMISTRY 2002; 7(-4-):297-300. >>> Olanzapine; risperidone; quetiapine fumerate; SC; Rat; Controls received mp w/ vehicle; antipsychotic agents.

5251 Tarazi, F.I., Zhang, K.H., Baldessarini, R.J. Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology 2002; 161(--):263-270. >>> Olanzapine; Risperidone; Quetiapine fumarate; SC; rat; controls received mp w/ vehicle; functionality of mp verified by residual volume; antipsychotic agents.

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7. Remoxipride

2828 Georgieva, J., Mohringe, B., Magnusson, O. Neurochemical effects of prolonged treatment with remoxipride as assessed by intracerebral microdialysis in freely moving rats. Prog. Neuro-Psychopharmacol. Biol. Psychiat 1994; 18(--):1187-1201. >>> Remoxipride HCl; Sodium chloride; SC; rat; 2002; controls received sodium chloride; functionality of mp verified by checking blood levels of drug and determining residual drug amount; comparison of sc injections vs mp; remoxipride is an antipsychotic drug.

2195 Ericson, H., Ross, S.B. Subchronic treatment of rats with remoxipride fails to modify sigma binding sites in the brain. Eur. J. Pharmacol. - Mol. Pharmacol. Sect 1992; 226(--):157-161. >>> Remoxipride HCl; Haloperidol; Water; Acetic acid; SC; rat; controls received sham operations.

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8. Risperidone

16041 Teng, B. L., Nikolova, V. D., Riddick, N. V., Agster, K. L., Crowley, J. J., Baker, L. K., Koller, B. H., Pedersen, C. A., Jarstfer, M. B., Moy, S. S. Reversal of social deficits by subchronic oxytocin in two autism mouse models. Neuropharmacology 2016; 105(--):61-71. >>> Risperidone; SC; Mice; 1002; 1007D; Controls received mp w/ vehicle; animal info (C58/J); pumps replaced every 14 days; behavioral testing (chamber choice task; acoustic startle test; marble burying assay);“This pump replacement allowed dosage to be adjusted for increased body weight during the chronic risperidone treatment.“ pg 62-63; Dose (2 mg/kg/day); used clozapine slow-release pellets because of drug solubility (pg.62);.

12201 Muly, E.C., Votaw, J.R., Ritchie, J., Howell, L.L. Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone. Journal of Pharmacology and Experimental Therapeutics 2012; 341(-1-):81-89. >>> Risperidone; paliperidone; Intragastric; Monkey; Animal info (male, Rhesus, 4.2-6.3 years old); pumps replaced; 2-week pump replaced with 4-week pump containing saline for a washout period. 4-week pump was then replaced with 2-week pump to continue dosing.

11592 Secher, A., Husum, H., Holst, B., Egerod, K.L., Mellerup, E. Risperidone Treatment Increases CB(1) Receptor Binding in Rat Brain. Neuroendocrinology 2010; 91(-2-):155-168. >>> Risperidone; Cyclodextrin, hydroxyoproyl beta; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (male, Sprague Dawley, 180-200 g); post op. care (Baytril); stress/adverse reaction:"infections"(see pg. 156); 20% cyclodextrin used;"We chose to administer risperidone through osmotic minipumps to ensure steady-state plasma levels and avoid plasma fluctuations observed with drug injections."pg 156.

8490 Lin, E.J.D., Lee, N.J., Slack, K., Karl, T., Duffy, L., O'Brien, E., Matsumoto, I., Dedova, I., Herzog, H., Sainsbury, A. Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats. Neuropharmacology 2006; 51(-7-8-):1129-1136. >>> Haloperidol; risperidone; Acetic acid; SC; Rat; 2ML4; Controls received mp w/ vehicle; no stress (see pg. 1131); half-life (p. 1131) 4-6 times shorter in rodents than in humans; post op. care (bupivicaine); animal info (male, Sprague-Dawley, 9-10 weeks old, 280-430 grams);"This dosing regimen also takes into consideration the reported 4-6 times shorter half-life of antipsychotic drugs in rodents than humans and highlights the advantage of using minipumps in the present study for continuous drug administration to achieve receptor occupancies comparable to clinical use in humans."(p. 1131).

8305 O'Brien, E., Dedova, I., Duffy, L., Cordwell, S., Karl, T., Matsumoto, I. Effects of chronic risperidone treatment on the striatal protein profiles in rats. Brain Research 2006; 1113(--):24-32. >>> Risperidone; Water, sterile; acetic acid; sodium hydroxide; SC; Rat; 2ML4; Controls received mp w/ vehicle; animal info (Sprague-Dawley, male, 357 grams; 11 weeks old); behavioral study.

6329 Kapur, S, Susan C. Antipsychotic Dosing in Preclinical Models is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on in Vivo Occupancy. Journal of Pharmacology and Experimental Therapeutics 2003; 305(-2-):625-631. >>> Haloperidol; olanzapine; risperidone; quetiapine; clozapine; Water; acetic acid, glacial; SC; Rat; 2ML2; Plasma levels taken; dose-response (p. 629); comparison of daily injections vs. chronic mp; half-life (p. 626) 2-4 hours; haloperidol and risperidone were dissolved in distilled water; olanzapine, quetiapine and clozapine were dissolved in 1% to 2% acetic acid; great dose information;"we propose that only administration by pump (or administration more than four times a day[injections]) can provide clinical-like occupancies for haloperidol, olanzapine, and risperidone."p. 630.

6072 Tarazi, F.I., Baldessarini, R.J., Kula, N.S., Zhang, K.H. Long-term effects of olanzapine, risperidone, and quetiapine on ionotropic glutamate receptor types: Implications for antipsychotic drug treatment. Journal of Pharmacology and Experimental Therapeutics 2003; 306(-3-):1145-1151. >>> Olanzapine; risperidone; quetiapine fumerate; SC; Rat; Functionality of mp verified by residual volume; antipsychotic drugs.

6027 Tarazi, F.I., Zhang, K.H., Baldessarini, R.J. Long-term effects of newer antipsychotic drugs on neuronal nitric oxide synthase in rat brain. NITRIC OXIDE-BIOLOGY AND CHEMISTRY 2002; 7(-4-):297-300. >>> Olanzapine; risperidone; quetiapine fumerate; SC; Rat; Controls received mp w/ vehicle; antipsychotic agents.

5251 Tarazi, F.I., Zhang, K.H., Baldessarini, R.J. Long-term effects of olanzapine, risperidone, and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain regions. Psychopharmacology 2002; 161(--):263-270. >>> Olanzapine; Risperidone; Quetiapine fumarate; SC; rat; controls received mp w/ vehicle; functionality of mp verified by residual volume; antipsychotic agents.

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9. Spiperone

1288 Shippenberg, T.S., Herz, A. Motivational effects of opioids; influence of D-1 versus D-2 receptors antagonists. Eur. J. Pharmacol 1988; 151(--):233-242. >>> Spiperone; SCH-23390; DMSO; Water; SC; rat; 2001; 2ML1; functionality of mp verified after delivery; dopamine antagonist.

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10. Sulpiride

2109 Zhou, L.-W., Zhang, S.-P., Welsh, S., Connell, T.A., Weiss, B. Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors. Eur. J. Pharmacol 1992; 218(--):219-227. >>> Quinpirole HCl; Sulpiride; Triazolam; Ascorbic acid; DMSO; SC; mice; 2001; Quinpirole is a dopamine agonist; antidepressant; stability verified in vitro for 7 days.

1443 Ueda, H. Time course study of changes in the activity of rats during intraventricular infusion of 6-hydroxydopamine, haloperidol and sulpiride: a study of the relationship between an origin of the negative symptoms in schizophrenia and catecholamines. J. Iwate Med. Assoc 1988; 40(-3-):385-398. >>> Dopamine, 6-hydroxy-; Haloperidol; Sulpiride; CSF/CNS; rat; Japanese, English abstract.

630 Costall, B., Domeney, A.M., Naylor, R.J. The continuity of dopamine receptor antagonism can dictate the long-term behavioural consequences of a mesolimibic infusion of dopamine. Neuropharmacology 1985; 2(-3-):193-197. >>> Dopamine HCl; Sulpiride; Nitrogen; Sodium metabisulfite; CSF/CNS (nucleus accumbens); IP; rat; mp model not stated; comparison of SULP ip injec vs. mp infusion; 2 mp/rat - bilateral infusion; mp primed overnight; vehicles listed used w/DOP; concomitant SULP admin. ip.

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11. Trifluoperazine

144 Dougherty Jr, G.G., Ellinwood Jr, E.H. Amphetamine behavioral toxicity: rotational behavior after chronic intrastriatal infusion. Biol. Psychiatry 1981; 16(-5-):479-488. >>> Trifluoperazine; Amphetamine sulfate, d-; Saline; CSF/CNS (corpus striatum); rat; caudate putamen.

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What researchers are saying ...

“Moreover, the replacement of pumps is a relatively simple surgical procedure (Prieskorn and Miller, 200). Allowing longer-term (> 1 month) experiments to be performed.” Shepherd et al., Hearing Research 2002;172:92-98.