Best clinical practice with ziprasidone IM: update after 2 years of experience

Acute agitation is a common psychiatric emergency often treated with intramuscular (i.m.) medication when rapid control is necessary or the patient refuses to take an oral agent. Conventional i.m. antipsychotics are associated with side effects, particularly movement disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon) is the first second-generation, or atypical, antipsychotic to become available in an i.m. formulation. Ziprasidone IM was approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2 years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasidone IM and offers recommendations on its use in various settings. In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15-30 minutes) reduction in agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with haloperidol i.m. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disorders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences. Transition from i.m. to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hypertension in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical setting are warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.     

The structure of childhood disruptive behaviors

Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) frequently co-occur. Comorbidity of these 2 childhood disruptive behavior domains has not been satisfactorily explained at either a structural or etiological level. The current study evaluated a bifactor model, which allows for a "g" factor in addition to distinct component factors, in relation to other models to improve understanding of the structural relationship between ADHD and ODD. Participants were 548 children (321 boys, 227 girls) between the ages of 6 years and 18 years who participated in a comprehensive diagnostic assessment incorporating parent and teacher ratings of symptoms. Of these 548 children, 153 children were diagnosed with ADHD (without ODD), 114 children were diagnosed with ADHD + ODD, 26 children were diagnosed with ODD (without ADHD), and 239 children were classified as non-ADHD/ODD comparison children (including subthreshold cases). ADHD symptoms were assessed via parent report on a diagnostic interview and via parent and teacher report on the ADHD Rating Scale. ODD symptoms were assessed via teacher report. A bifactor model of disruptive behavior, comprising a "g" factor and the specific factors of ADHD and ODD, exhibited best fit, compared to 1-factor, 2-factor, 3-factor, and 2nd-order factor models of disruptive behaviors. It is concluded that a bifactor model of childhood disruptive behaviors is superior to existing models and may help explain common patterns of comorbidity between ADHD and ODD.     

External Validation of Bifactor Model of ADHD: Explaining Heterogeneity in Psychiatric Comorbidity,Cognitive Control,and Personality Trait Profiles Within DSM-IV ADHD

The current paper provides external validation of the bifactor model of ADHD by examining associations between ADHD latent factor/profile scores and external validation indices. 548 children (321 boys; 302 with ADHD), 6 to 18 years old, recruited from the community participated in a comprehensive diagnostic procedure. Mothers completed the Child Behavior Checklist, Early Adolescent Temperament Questionnaire, and California Q-Sort. Children completed the Stop and Trail-Making Task. Specific inattention was associated with depression/withdrawal, slower cognitive task performance, introversion, agreeableness, and high reactive control; specific hyperactivity-impulsivity was associated with rule-breaking/aggressive behavior, social problems, errors during set-shifting, extraversion, disagreeableness, and low reactive control. It is concluded that the bifactor model provides better explanation of heterogeneity within ADHD than DSM-IV ADHD symptom counts or subtypes.     

Parents' personality and infants' temperament as contributors to their emerging relationship

The authors examined the contributions of infant's temperament and parent's personality to their relationship. In Study 1, 102 infants, mothers, and fathers were studied when infants were 7 months; in Study 2, 112 infants and mothers were followed from 9 to 45 months. Infants' temperament (joy, fear, anger, and attention) was observed in standard temperament paradigms. Parents' personality measures encompassed the Big Five traits and Empathy in Study 1 and Mistrust, Manipulativeness, Aggression, Dependency, Entitlement, and Workaholism in Study 2. Parent-child relationship (shared positive affect and parental responsiveness in Studies 1 and 2 and parental tracking of the infant in Study 1) was observed in naturalistic contexts. In Study 1, mothers' Neuroticism, Empathy, and Conscientiousness and fathers' Agreeableness, Openness, and Extraversion related to the relationship with the infants. All measures of infant temperament also related to the emerging relationship. In Study 2, maternal Mistrust, Manipulativeness, Dependency, and Workaholism predicted the relationship with the child.     

Sex Differences in the Pathway from Low Birth Weight to Inattention/hyperactivity

Inattention/hyperactivity is a childhood outcome of low birth weight. However, the mechanisms by which low birth weight leads to inattention/hyperactivity are unclear. This study examined arousal, activation, motor speed, and motor coordination as possible mechanisms, attending to sex differences. 823 children (400 males) from Detroit and surrounding suburbs were assessed with the Child Behavior Checklist and the Teacher Report Form and completed experimental tasks to assess vigilance and activation (Continuous Performance Test signal detection parameters) and motor output speed and control (Grooved Pegboard) at 6 years of age. The relationship between birth weight and inattention/hyperactivity was slightly, but not significantly, stronger for boys than for girls. Arousal, motor speed, and motor coordination significantly partially mediated the relationship between birth weight and inattention/hyperactivity for boys and girls. Moderated mediation was found for the pathway between motor coordination and inattention/hyperactivity such that this relationship was stronger for boys than for girls. Sex differences in the associated features of attention symptoms may reflect partially distinct etiological pathways.     

A randomized, controlled clinical trial of in virtuo and in vivo exposure for spider phobia

The present study compared the efficacy of virtual reality (VR) in virtuo exposure and in vivo exposure in the treatment of spider phobia. Two treatment conditions were compared to a waiting-list condition. A 3-month follow-up evaluation was conducted in order to assess the durability of the treatment effects. Participants were randomly assigned to the treatment groups. A total of 16 participants received the in virtuo treatment, and 16 received the in vivo treatment. The waiting-list condition included 11 participants. Participants received eight 1.5-hour treatment sessions. Efficacy was measured with the Fear of Spiders Questionnaire, the Spider Beliefs Questionnaire (SBQ-F), and a Behavioral Avoidance Test (BAT). In addition, a clinician administered the Structured Interview for DSM-IV to assess DSM-IV's criteria for specific phobia and severity. Clinical and statistically significant improvements were found for both groups. Differences in treatment groups were found on one of five measures of fear: greater improvement on the SBQ-F beliefs subscale was associated with in vivo exposure.     

Verbal Working Memory as a Longitudinal Mechanism of Vocabulary Problems in Preschoolers with ADHD

Elucidation of early potential risk factors of Attention-Deficit/Hyperactivity Disorder (ADHD) is important to allow for early identification of ADHD and targeted early intervention for children with ADHD. Delayed language skills, particularly poor vocabulary, is an early-developing potential risk factor that is thought to be involved in developmental pathways to ADHD; however, mechanisms explaining the relationship between poor vocabulary skills and ADHD symptoms are unclear and warrant investigation. The present study examines the relationship between poor vocabulary skills and ADHD symptoms by testing cognitive mechanisms, namely verbal working memory (WM), that might account for this link. Participants were 109 young children between the ages of three and six and their primary caregivers. Diagnostic information on ADHD symptoms was available from parents and teachers/daycare providers via standardized rating forms. Vocabulary skills and WM were measured through child performance on laboratory tasks. Mediation analyses found poor verbal working memory significantly partially explained the vocabulary-ADHD association for both parent and teacher-rated ADHD symptoms. Further, effects of verbal WM on the association between poor vocabulary and increased ADHD symptoms largely held at one-year follow-up. Development of early interventions targeting verbal WM may be a promising new direction for early ADHD intervention work.     

The rooting reflex as an infant feeding cue

Experts in infant health and development consider the rooting reflex a cue of a baby's hunger and recommend feeding the infant when this reflex occurs. However, the relation between rooting and infant feeding status has not been well established in the literature. In the current study, seven parents documented the occurrence of their newborns' rooting, crying, and a control reflex (palmar grasp) before, after, and between naturally occurring feedings. For all participants, rooting occurred during a greater percentage of reflex checks prior to feedings, whereas the palmar grasp occurred during a similar percentage of checks across these time periods. These results provide empirical support for the rooting reflex as a feeding cue. However, data for only one dyad suggested a high probability of the rooting reflex occurring without crying during prefeeding checks. Thus, our data do not provide evidence that feeding in response to the rooting reflex would preempt infant crying.     

Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component hypotheses were that (a) maladaptive traits would increase risk for inattention/hyperactivity, (b) inattention/hyperactivity would increase risk for disruptive behaviors, and (c) disruptive behaviors would lead to adolescent substance abuse. Participants were 674 children (486 boys) from 321 families in an ongoing, longitudinal high risk study that began when children were 3 years old. Temperament traits assessed were reactive control, resiliency, and negative emotionality, using examiner ratings on the California Q-Sort. Parent, teacher, and self ratings of inattention/hyperactivity, disruptive behaviors, and substance abuse were also obtained. Low levels of childhood reactive control, but not resiliency or negative emotionality, were associated with adolescent substance abuse, mediated by disruptive behaviors. Using a cascade model, family risk for substance abuse was partially mediated by reactive control, inattention/hyperactivity, and disruptive behavior. Some, but not all, temperament traits in childhood were related to adolescent substance abuse; these effects were mediated via inattentive/hyperactive and disruptive behaviors. This work was supported by NIAAA grant R01-AA12217 to Robert Zucker and Joel Nigg, NIAAA grant R37-AA07065 to Robert Zucker and Hiram Fitzgerald, and NIMH grant R01-MH59105 to Joel Nigg. Martel was supported by 1 F31 MH075533-01A2. The authors thank the participants and Susan Refior, the long term MLS Field Director, whose steadfast commitment and support have made this study possible.     

Stimulation of hippocampal adenylyl cyclase activity dissociates memory consolidation processes for response and place learning

Procedural and declarative memory systems are postulated to interact in either a synergistic or a competitive manner, and memory consolidation appears to be a highly critical stage for this process. However, the precise cellular mechanisms subserving these interactions remain unknown. To investigate this issue, 24-h retention performances were examined in mice given post-training intrahippocampal injections of forskolin (FK) aiming at stimulating hippocampal adenylyl cyclases (ACs). The injection was given at different time points over a period of 9 h following acquisition in either an appetitive bar-pressing task or water-maze tasks challenging respectively "response memory" and "place memory." Retention testing (24 h) showed that FK injection altered memory formation only when given within a 3- to 6-h time window after acquisition but yielded opposite memory effects as a function of task demands. Retention of the spatial task was impaired, whereas retention of both the cued-response in the water maze and the rewarded bar-press response were improved. Intrahippocampal injections of FK produced an increase in pCREB immunoreactivity, which was strictly limited to the hippocampus and lasted less than 2 h, suggesting that early effects (0-2 h) of FK-induced cAMP/CREB activation can be distinguished from late effects (3-6 h). These results delineate a consolidation period during which specific cAMP levels in the hippocampus play a crucial role in enhancing memory processes mediated by other brain regions (e.g., dorsal or ventral striatum) while eliminating interference by the formation of hippocampus-dependent memory.