Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry.

Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond substantially to treatment with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal circuits, particularly those components modulated by dopamine. We developed a new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. Relaxation times strongly correlated with the child's capacity to sit still and his accuracy in accomplishing a computerized attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with attention-deficit/hyperactivity disorder, although the magnitude and direction of the effect was strongly dependent on the child's unmedicated activity state. There was a similar but nonsignificant trend in the right caudate. T2 relaxation time measures in thalamus did not differ significantly between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity disorder symptoms may be closely tied to functional abnormalities in the putamen, which is mainly involved in the regulation of motor behavior.

Lux vs. wavelength in light treatment of Seasonal Affective Disorder.

OBJECTIVE: Published dosing guidelines for treatment of Seasonal Affective Disorder (SAD) refer to photopic lux, which is not appropriate for short-wavelength light. Short wavelengths are most potent for many non-visual responses to light. If SAD therapy were similarly mediated, standards utilizing lux risk overestimating necessary dose. We investigated antidepressant responses to light using two light-emitting diode (LED) sources, each emitting substantial short-wavelength light, but <2500 lux. METHOD: A randomized, double-blind trial investigated 3-week 45 min/day out-patient treatment with blue-appearing (goLITE) or blue-enriched white-appearing light in 18 moderately-depressed adults (12F, 49.1 +/- 9.5 years). Equivalent numbers of photons within the short-wavelength range were emitted, but the white source emitted twice as many photons overall and seven-fold more lux. RESULTS: Depression ratings (SIGH-ADS; http://www.cet.org) decrease averaged 82% (SD = 17%) from baseline (P < 0.0001) in both white- and blue-light groups. Both sources were well tolerated. CONCLUSION: Short-wavelength LED light sources may be effective in SAD treatment at fewer lux than traditional fluorescent sources.

Are short (blue) wavelengths necessary for light treatment of seasonal affective disorder?

Despite widely published speculation regarding a potential potency advantage of short-wavelength (blue-appearing) light for Seasonal Affective Disorder (SAD) treatment, there have been few systematic studies. Those comparing short-wavelength to broad-wavelength (white) light under actual clinical conditions suggest equivalent effectiveness. This multicenter, parallel-group design trial was undertaken to compare the effects of light therapy on SAD using blue (~465 nm) versus blue-free (595-612 nm) LED lights. Fifty-six medication-free subjects aged 21-64 years who met DSM-IV-TR criteria for recurrent major depression with winter-type seasonal pattern were enrolled in this blinded study at five participating centers between January and March 2012. Thirty-five subjects met the criteria for randomization to 30 min of either blue (~465 nm) or blue-free (595-612 nm) daily morning light therapy. Twenty-nine subjects completed the study; three subjects withdrew due to treatment-related adverse events, including migraines, and three withdrew for non-study-related reasons. The primary effectiveness variable was depression score (SIGH-ADS) after six weeks of daily light treatment. Secondary effectiveness variables included quality-of-life (QoL) and suicidality ratings. Using an intent-to-treat analysis, mean depression scores were different at baseline for the blue group (29 ± 5 versus 26 ± 5, p = 0.05 blue versus blue-free, respectively), and the initial score was used as a covariate. Baseline scores were not significantly different between treatment groups among those who completed the study, and no significant differences in depression scores were observed after 6 weeks (mean ± SD scores at 6 weeks: 5.6 ± 6.1 versus 4.5 ± 5.3, p = 0.74, blue versus blue-free, respectively). In addition, the proportion of subjects who met remission criteria, defined as a depression score ≤8, was not significantly different between the two groups (p = 0.41); among the 29 subjects who completed the study, 76% of subjects experienced remission by the end of the trial, which coincided with the beginning of spring. The QoL and suicidality ratings were also significantly improved from pre- to post-treatment, with no significant difference between treatments. No subject experienced worsening or non-improved symptoms over the 6-week trial. The main finding of this study is that subjects treated with blue light did not improve more than subjects treated with blue-free light; both showed substantial improvement on multiple measures. Failure to find differences may have resulted from methodological constraints, including a small sample size. Recruitment began mid-winter during an unusually mild season, and the trial was terminated earlier than planned by the study sponsor due to a failure to detect a difference. However, if confirmed in a larger randomized sample, these results suggest that blue wavelengths are not necessary for successful SAD treatment.

Circadian rest-activity disturbances in seasonal affective disorder.

BACKGROUND: Previous studies hypothesized that seasonal affective disorder (SAD) was caused by a circadian rhythm abnormality. The purpose of this study was to ascertain whether rest-activity rhythms were phase delayed, diminished in amplitude, or more poorly entrained to the 24-hour day. METHOD: Twenty healthy adult controls and 25 outpatients meeting Rosenthal-National Institute of Mental Health criteria for SAD and DSM-III-R criteria for major or bipolar depression with seasonal pattern had their levels of activity recorded for 72 hours (weekdays) using wrist-worn actigraphs. RESULTS: Subjects with SAD had activity levels that were 11% lower than controls (P = .03), and their levels of activity were most attenuated during the first 2 hours after arising (P = .004). The relative amplitude of the circadian rhythm did not differ between groups. Patients with SAD were phase delayed by 50 minutes for the entire period (P = .02). Analysis of each individual day indicated that patients were delayed by up to 70 minutes (P = .007). Interdaily stability, an index of coupling between the rhythm and its zeitigeber was reduced in SAD (P = .01). Compared with controls, patients with SAD had best-fit circadian periods that were 92% more deviated from 24 hours (P = .007) and daily acrophase (time of the peak of the fit circadian rhythm) times that were 110% more variable between days (P < .001). CONCLUSIONS: Patients with SAD have circadian rest-activity rhythms that are significantly phase delayed and more poorly entrained to the 24-hour day.

The phototherapy light visor: more to it than meets the eye.

OBJECTIVE: The purpose of the study was to ascertain whether phototherapy light visors provide an effective treatment for seasonal affective disorder. Previous studies have demonstrated a moderate response rate but have failed to find any difference in efficacy between light intensities. METHOD: Subjects were randomly assigned to receive, over a 2-week treatment period, 30 minutes of morning phototherapy with a light visor that emitted either a dim (30-lux) red light or a bright (600-lux) white light. Raters were blind to treatment, and patients were unaware of the alternatives. Response was assessed by using the structured 21-item Hamilton Depression Rating Scale, with an eight-item addendum for atypical depressive symptoms. Fifty-seven patients were enrolled across two sites. RESULTS: Patients assigned to the different visors had similar baseline depression scores and similar expectations of outcome. Hamilton depression scale scores declined by 34.6% for subjects given bright white light and by 40.9% for subjects given dim red light. Scores for atypical depressive symptoms fell by 44.1% for patients assigned the bright white light visors and by 49.0% for patients assigned the dim red light visors. Altogether, 39.3% of the patients who received red light and 41.4% of the patients who received bright white light showed a full clinical response. CONCLUSIONS: There were no significant differences in therapeutic response between patients who were treated with red or white light. The results of this study suggest that the phototherapy light visor may function as an elaborate placebo. Alternative explanations, however, are considered.

Antidepressant drugs and the emergence of suicidal tendencies.

Although antidepressant medications represent the cornerstone of treatment for patients with moderate to severe clinical depression, they also carry serious risks. There is evidence which suggests that antidepressants can, in rare instances, induce or exacerbate suicidal tendencies. Nine clinical mechanisms have been proposed through which this may occur. These are: (a) energizing depressed patients to act on pre-existing suicidal ideation; (b) paradoxically worsening depression; (c) inducing akathisia with associated self-destructive or aggressive impulses; (d) inducing panic attacks; (e) switching patients into manic or mixed states; (f) producing severe insomnia or interfering with sleep architecture; (g) inducing an organic obsessional state; (h) producing an organic personality disorder with borderline features; and (i) exacerbating or inducing electroencephalogram (EEG) or other neurological disturbances. Epidemiological and controlled studies also provide data on the association between antidepressant drugs and suicidal ideation, attempts and fatalities. These include studies which: (a) suggest that electroconvulsive therapy may be more effective than antidepressant drugs in reducing the frequency of suicide attempts; (b) indicate that antidepressants may differ in their capacity to reduce the frequency of suicide attempts; (c) find that more overdose attempts were made by patients receiving maprotiline than placebo; and (d) suggest that fluoxetine may be associated with a greater risk of inducing de novo suicidal ideation. Evidence suggests that antidepressants may vary by at least 15-fold in the number of fatal overdoses per million prescriptions. Estimated overdose proclivity rates were derived after adjusting the fatal toxicity data by the therapeutic index of the drug. These rates were very consistent between agents with the same pharmacological properties, and correlated well with known overdose risk rates for amitriptyline, mianserin and maprotiline. Estimated overdose proclivity rates suggest that the highly selective noradrenaline (norepinephrine) uptake inhibitors (desipramine, nortriptyline, maprotiline) may be associated with a greater risk for overdose than more mixed uptake inhibitors and monoamine oxidase inhibitors (MAOIs). Antidepressants are not uniformly neutral in regard to suicidal ideation and attempts. Data clearly demonstrate that antidepressants ameliorate suicidal ideation more effectively than placebo in patients with depression. Although antidepressants diminish suicidal ideation in many recipients, about as many patients experience worsening suicidal ideation on active medication as they do on placebo. Furthermore, at least as many patients attempted suicide on fluoxetine and tricyclic antidepressants as on placebo, and more patients attempted to overdose on maprotiline than placebo. These observations suggest that antidepressants may redistribute suicide risk, attenuating risk in some patients who respond well, while possible enhancing risk in others who respond more poorly.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between early abuse, posttraumatic stress disorder, and activity levels in prepubertal children.

OBJECTIVE: To examine the relationship between early physical and sexual abuse, posttraumatic stress disorder (PTSD), major depression, and activity levels in prepubertal children. METHOD: Nineteen unmedicated children with documented abuse (9.4 +/- 2.3 years; 6 girls, 13 boys) were compared with 15 healthy controls (8.3 +/- 1.9 years; 6 girls, 9 boys). Diagnoses were derived from structured interviews (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version). Motionlogger actigraphs collected activity data for 72 continuous hours in 1-minute epochs. RESULTS: Overall, abused children were 10% more active than normal children (p < .05) and displayed a paucity of periods of low-level daytime activity (p < .01). Abused children with PTSD were largely responsible for the increase in activity. Abused children with PTSD had a robust and normal circadian activity rhythm. Abused children in whom PTSD failed to develop had an attenuated circadian amplitude compared with subjects with PTSD (101% versus 93%, p < .01) and were phase-delayed by 61 minutes versus controls (p = .01). Early onset of abuse was significantly associated with greater likelihood of the development of PTSD and hyperactivity. Later age of abuse was associated with circadian dysregulation. CONCLUSIONS: These preliminary observations indicate that abused children with PTSD have activity profiles similar to those of children with attention-deficit hyperactivity disorder, while abused children without PTSD have activity profiles more similar to those of depressed children.

Objective measurement of hyperactivity and attentional problems in ADHD.

OBJECTIVE: To precisely describe movement abnormalities in seated children with attention-deficit hyperactivity disorder (ADHD) while they were engaged in a continuous performance task (CPT). METHOD: Diagnoses were made by using structured interviews (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version) and DSM-IV criteria. Movement patterns of 18 boys with ADHD (9.3 +/- 2.4 years) and 11 normal controls (8.6 +/- 1.8 years) were recorded using an infrared motion analysis system that tracked the position of four markers 50 times per second to a resolution of 0.04 mm. RESULTS: Boys with ADHD moved their head 2.3 times more often than normal children (p < .002), moved 3.4 times as far (p < .01), covered a 3.8-fold greater area (p < .001), and had a more linear and less complex movement pattern (p < .00004). They responded more slowly and with greater variability on the CPT. Complexity of head movement and variability in response latency significantly correlated with teacher ratings. A predefined composite of movement and attention discriminated 16 of 18 patients from 11 of 11 controls. CONCLUSIONS: The relative inability of boys with ADHD to sit still can be objectively verified, and "fidgeting" appears to consist of more frequent, larger amplitude, whole body movements.

Increased nocturnal activity and impaired sleep maintenance in abused children.

OBJECTIVE: Previous studies have suggested that sleep disturbance may be the "hallmark of posttraumatic stress disorder," although several investigations have failed to find evidence for sleep disruption. The purpose of this study was to determine whether intense averse stimulation during early development, in the form of physical and/or sexual abuse, led to disruption of sleep and nocturnal activity. METHOD: Nineteen prepubertal children with documented abuse were compared with 15 nonabused normal controls and 10 depressed children. All subjects received a complete semistructured diagnostic interview. Ambulatory activity monitoring was used to evaluate sleep-related activity for three consecutive nights. Data were analyzed for nocturnal activity and algorithmic estimation of sleep initiation and continuity. RESULTS: Abused subjects were twice as active at night as normal and depressed children, and abused subjects emitted a greater percentage of their total daily activity during the night. Actigraph-derived sleep measures suggested that abused children had prolonged sleep latency and decreased sleep efficiency. Physically abused children had more impaired sleep efficiency than sexually abused children. CONCLUSION: Abused children have higher levels of nocturnal activity than normal controls or depressed children and appear to have more difficulty falling and staying asleep. Physical abuse appears to be the salient factor rather than posttraumatic stress disorder.

Locomotor activity in depressed children and adolescents: I. Circadian dysregulation.

OBJECTIVE: To determine whether circadian activity rhythms were altered in pediatric patients with depression. Evidence was sought for a shift in the timing of the rhythm, blunting of circadian amplitude, or emergence of noncircadian periodicities. METHOD: Locomotor activity was quantified in 57 patients with major depressive mood disorders (mean age 12.4 years) and 16 normal controls (9.9 years). Activity was measured in 5-minute epochs during 72 hours using belt-worn electronic activity monitors. RESULTS: Patients with mood disorders displayed a 15% decrease in the amplitude of their circadian rhythm, and a 52% increase in the magnitude of their twice-daily (hemicircadian) rhythm. No significant difference emerged in the timing of the circadian rhythm. Depressed inpatients and outpatients displayed comparable disturbances, which were most marked in adolescents. CONCLUSIONS: Circadian activity rhythms were dysregulated in pediatric patients with major depression. These findings may have etiological and diagnostic significance.

Modifying quiet room design enhances calming of children and adolescents.

OBJECTIVE: To determine whether altering design of a quiet room (QR) produced more rapid calming of agitated or aggressive hospitalized children. METHOD: One of five similar QRs was modified by painting the white walls tea rose, carpeting the vinyl floor, and painting a picturesque mural on one wall. The effects of these modifications were assessed in 19 patients (mean age = 9.6 years), using a within-subjects, repeated-measures design. Overt Aggression ratings were made at the time of placement, and at 5-minute intervals thereafter, until the child was dismissed. Children were blind to the fact that a study was being conducted; raters and staff were not. RESULTS: Total aggression ratings were 45% lower in the modified QR than in the standard QR (p < .03), and initial aggression scores fell by 50% during 5 minutes of placement in the modified QR, but only after 20 minutes of placement in the standard QR (p < .0001). Motor excitement and verbal aggression were the two component factors most strongly influenced by QR design. CONCLUSION: This preliminary report suggests that it may be possible to modify QRs to facilitate calming of aggressive, agitated children and provides preliminary support for redesign of QRs.

Circadian rest-activity disturbances in children with seasonal affective disorder.

OBJECTIVE: Seasonal affective disorder (SAD) affects from 1.7% to 5.5% of children. Previous studies found that nonseasonally depressed children had a blunted circadian rhythm, while adults with SAD had a delayed and poorly entrained rhythm. The purpose of this study was to determine whether pediatric SAD more closely resembles nonseasonal pediatric depression or adult SAD. METHOD: Twelve normal, healthy volunteers (11.6 +/- 3.7 years; 6 female, 6 male) and 14 unmedicated children with SAD (11.0 +/- 3.3 years; 9 female, 5 male) meeting Rosenthal/NIMH criteria for SAD and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version criteria for major depression had their levels of activity recorded for 72 hours (weekdays) using belt-worn actigraphs. RESULTS: The SAD group had blunted circadian amplitudes that were 10% lower than normal (p = .004). They were more poorly modeled by the standard cosinor equation (p = .001), and a circadian rhythm accounted for 39% less of the variability in their activity profile (p = .007). The amplitude of the 12-hour harmonic rhythm was markedly increased. There were no differences between SAD and control children in the timing of the circadian rhythm and degree of entrainment. CONCLUSIONS: Children with SAD displayed dysregulated circadian activity rhythms comparable with those reported in nonseasonally depressed children, yet different from those observed in adults.

Motor activity and severity of depression in hospitalized prepubertal children.

OBJECTIVE: To determine whether there is an association between activity levels and the severity and nature of depressive symptoms. METHOD: Locomotor activity was quantified in 27 consecutively selected hospitalized prepubertal children. Activity was measured in 5-minute epochs over a period of 72 hours using belt-worn monitors. Depressive symptoms were rated using the Children's Depression Rating Scale-Revised, the Children's Depression Inventory, and an observer rating scale for nursing staff. RESULTS: Measures of reduced daytime activity correlated with scores on the Children's Depression Rating Scale and the observer rating scale, but not the Children's Depression Inventory. Stepwise regression indicated that the strongest association occurred between a composite measure of severity, age, and percentage of low-level diurnal activity periods (r = .724, p < .0005). Activity measures correlated with clinical ratings of sadness, low self-esteem, anhedonia, and physical complaints, and to a lesser degree with ratings of hypoactivity, fatigue, and slow speech. CONCLUSIONS: Reduced levels of activity correlated significantly with clinical ratings of depressive severity across diagnostic groups. The development of objective measures of depressive severity may have prognostic and therapeutic implications.

A controlled trial of light therapy for the treatment of pediatric seasonal affective disorder.

OBJECTIVE: To evaluate the efficacy of light therapy for the treatment of pediatric seasonal affective disorder (SAD). METHOD: 28 children (aged 7 to 17 years) at two geographically distinct sites were enrolled in a double-blind, placebo-controlled, crossover trial of bright-light treatment. Subjects initially entered a week-long baseline period during which they wore dark glasses for an hour a day. They were then randomly assigned to receive either active treatment (1 hour of bright-light therapy plus 2 hours of dawn simulation) or placebo (1 hour of clear goggles plus 5 minutes of low-intensity dawn simulation) for 1 week. The treatment phase was followed by a second dark-glasses phase lasting 1 to 2 weeks. After this phase, the children received the alternate treatment. Response was measured using the parent and child versions of the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders version (SIGH-SAD). RESULTS: Data were analyzed as change from baseline. SIGH-SAD-P total depression scores were significantly decreased from baseline during light therapy compared with placebo (one-way analysis of variance, rho = .009), and no differences were found between the placebo and control phases. Subscores of atypical and typical depression were also significantly decreased during the active treatment (rho = .004 and .028, respectively). A similar trend was noted with the SIGH-SAD-C, but this did not reach significance. At the end of the study, 78% of the parents questioned and 80% of the children questioned rated light therapy as the phase during which the child "felt best." CONCLUSION: Light therapy appears to be an effective treatment for pediatric SAD.

Light visor treatment for seasonal affective disorder: a multicenter study.

The effectiveness of light therapy in seasonal affective disorder (SAD) was evaluated in 105 subjects across five centers. Three intensities of light (60 lux, 600 lux, and 3500 lux) were used in a 2-week randomized, parallel design. There was no significant difference in antidepressant efficacy of the three intensities of light. All three intensities produced a similar frequency of antidepressant response to each other and to that reported in previous studies. There were site differences in the severity of depression during light treatment, but diagnosis and medication status did not affect antidepressant response. These findings suggest that light therapy has an antidepressant action by a nonspecific effect or that light is biologically active in the treatment of SAD across a wide range of intensities.

Psychopharmacology and clinical practice.

Options for pharmacotherapy are varied and at times idiosyncratic. Although clear treatment strategies exist for some patients, others are left with only partial relief and substantial side effects. Newer agents have been accompanied by a great deal of interest and hope but fail to be the panacea or "cure." As sensitive caregivers with an eclectic framework, grounded in a variety of different theoretical approaches, we can be hopeful about the advantages and promise of what medications hold, yet help balance reality and potential pitfalls.