benztropine and Attention-Deficit-Disorder-with-Hyperactivity

In this report, we discuss the case of a 9-year-old male with Attention Deficit Hyperactivity Disorder (ADHD) on long-term methylphenidate and guanfacine who experienced acute orofacial dystonia that resolved immediately with the administration of benztropine. Current literature describes various cases of methylphenidate-induced dystonia, but ours appears to be the first reported instance of spontaneous dystonia without a recent change in dose or medication change. This may suggest the possibility of methylphenidate-induced dystonia spontaneously occurring several years after initiation.

Topics: Attention Deficit Disorder with Hyperactivity; Benztropine; Central Nervous System Stimulants; Child; Dystonia; Guanfacine; Humans; Male; Methylphenidate

Methylphenidate and d-amphetamine, medications used for treatment of attention deficit hyperactivity disorder (ADHD), are used recreationally and self-administered by laboratory animals. Benztropine (BZT) analogs, like those medications, increase synaptic dopamine levels but are less effective in maintaining self-administration, suggesting clinical utility with less abuse liability.. The current study was designed to evaluate potential therapeutic effects of BZT analogs related to ADHD.. Rats responded under a delay-discounting procedure in which responses on one lever produced immediate delivery of a single food pellet and alternative responses produced four food pellets either immediately or with various temporal delays, with those delays arranged in ascending or random orders in different groups of rats. Selection of the smaller more immediate reinforcer has been suggested as an aspect of "impulsivity," a trait with suggested involvement in ADHD. Other rats were studied under fixed-interval (FI) 300-s schedules to assess drug effects on behavior under temporal control.. d-Amphetamine, methylphenidate, and the BZT analog AHN 1-055, but not AHN 2-005 or JHW 007, increased selection of the large, delayed reinforcer with either arrangement of delays. All drugs changed the temporal distribution of responses within the FI from one with responses concentrated at the end to a more uniform distribution. Changes in the temporal distribution of FI responding occurred with drugs that did not affect discounting suggesting that discounting does not arise directly from the same temporal control processes controlling FI responding.. AHN 1-055 may be of clinical utility in the treatment of ADHD.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Benztropine; Conditioning, Operant; Delay Discounting; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Impulsive Behavior; Male; Rats; Rats, Sprague-Dawley; Self Administration

Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Benztropine; Cognition; Cognition Disorders; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Extracellular Fluid; Male; Memory, Short-Term; Neurons; Nootropic Agents; Norepinephrine; Nucleus Accumbens; Prefrontal Cortex; Random Allocation; Rats; Rats, Sprague-Dawley; Septal Nuclei; Spatial Behavior

Extrapyramidal symptoms (EPSs) (dystonic reaction, rigidity, and akathisia) occur as a result of D2 receptor blockade. Selective serotonin-reuptake inhibitors (SSRIs) have been reported to induce extrapyramidal signs and symptoms but tricyclic antidepressants have been rarely reported. Among the side effects attributed to valproic acid administration, the production of EPS is very rare, particularly in children. In this paper we present a case (10-year-old girl) under multiple pharmacologic treatment who developed EPSs (oculogyric crisis) shortly after the adjunct of imipramine to a combination of methylphenidate and valproic acid. Oculogyric crisis occurred on the third day of this combination treatment and these symptoms included ocular pain and sustained upward gaze. Benztropine 2 mg i.m. resulted in rapid relief of oculogyric crisis symptoms.

Topics: Attention Deficit Disorder with Hyperactivity; Benztropine; Bipolar Disorder; Child; Comorbidity; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Humans; Imipramine; Injections, Intramuscular; Methylphenidate; Neurologic Examination; Ocular Motility Disorders; Psychotropic Drugs; Valproic Acid