Faculty Bibliography

Attention-deficit/hyperactivity disorder (ADHD), once considered to be a childhood disorder, is diagnosed in similar to 7 million adults in the United States, as reported by The National Comorbidity Study. Although it is now recognized that ADHD often persists into adulthood, the current diagnostic criteria is geared toward symptom identification in children. Symptoms of inattention, impulsivity, and hyperactivity evolve over the life cycle and present differently in adults. Further complicating diagnosis is that ADHD is associated with multiple functional impairments and comorbid psychiatric disorders. The Multi-Modal Treatment Study of ADHD reported that only 32% of the study population had ADHD alone; 29% had ADHD plus oppositional defiant disorder and/or conduct disorder, 14% had ADHD plus anxiety or depression, and 25% had all three disorders. Optimal treatment utilizes a multimodal approach including behavioral treatments combined with pharmacologic treatment strategies. Food and Drug Administration-approved medications for ADHD include the stimulants and nonstimulants, although tricyclic antidepressants and bupropion are also commonly used. In this monograph, Craig L. Donnelly, MD, reviews the history of ADHD and discusses the pathophysiologic progression of childhood symptoms into those commonly exhibited by adults. Next, Frederick W. Reimherr, MD, reviews comorbidity of ADHD and describes the Utah Criteria as a method of diagnosing adults through recollection of childhood problems. Finally, Joel L. Young, MD, reviews treatment approaches to adult ADHD and its comorbid conditions.

BACKGROUND:Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS:This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS:At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS:This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

Anticonvulsants are frequently used in the treatment of psychiatric conditions. In general, abrupt discontinuation of these drugs is contraindicated due to concerns about withdrawal symptoms. In a recent report, an 80-year-old woman developed delirium with focal brain splenial edema 8 days after having abruptly discontinued pregabalin, an analogue of gabapentin. While the causality is unsubstantiated at this point, the finding of focal brain edema in association with abrupt discontinuation of pregabalin ought to be a caution to clinicians about the importance of using tapering strategies when discontinuing pregabalin as well as other anticonvulsants.

Presents a report of a patient with epilepsy and testicular cancer in whom the chemotherapy agent, cisplatin, resulted in reduced levels and efficacy of valproic acid, culminating in a recurrence of severe, generalized, tonic-clonic seizures. Regardless of the mechanism of this interaction, clinicians who prescribe valproic acid ought to be aware of the possibility of cisplatin-induced reduction of serum valproic acid levels, and the associated loss of medication efficacy with reemergence of the underlying condition.

Reports the case of a 54-year-old woman with generalized anxiety disorder and complicated bereavement reaction who developed mirtazapine-induced arthralgia with an additional association to coagulopathy. While these side effects appear relatively uncommon, clinicians who prescribe mirtazapine ought to be aware of the possibility of their occurrence.

Three cases are reported that documents patients with bipolar disorder (aged 31, 37 and 32 years) in whom mirtazapine was used successfully to treat acute neuroleptic induced akathisia. If these results are confirmed, it is likely that these effects derive principally from mirtazapine's blockade of 5-HT-sub(2A/2C) receptors, which may disinhibit dopamine release in nigrostriatal projections. Large scale, double-blind, placebo-controlled clinical trials are needed to further validate these findings.

Milnacipran is a cyclopropane derivative which acts by inhibiting norepinephrine and serotonin reuptake at presynaptic sites. Three women (aged 27, 27 and 29 years) with premenstrual dysphoric disorder (PMDD) and intolerant to selective serotonin reuptake inhibitors (SSRIs) were successfully treated with milnacipran. These cases suggest that milnacipran is an effective agent, with minimal side effects and a low propensity to cause drug-drug interactions, for SSRI intolerant PMDD.

Previous 'Psychopharmacology Reviews' columns have discussed emerging studies in psychopharmacogenomics, which correlate the variability of patient responses to psychotropic drugs to individual genetic differences. A recent report showed a 74-year-old patient with the cytochrome P450 (CYP) 2D6 *5/*10 genotype, associated with defective CYP 2D6 metabolism, which rendered him particularly susceptible to prominent risperidone induced extrapyramidal symptoms. With respect to risperidone, CYP 2D6-defective or poor metabolizers, such as the patient described above, are at increased risk for toxicity at conventional doses due to elevated serum levels of risperidone and of its principal metabolite, 9-hydroxyrisperidone. Conversely, in ultrarapid CYP 2D6 metabolizers, the concentrations of risperidone and of 9-hydroxyrisperidone will be very low. Accurately identifying these individuals would likely be of value to predict nonresponse with conventional risperidone doses, as well as to exclude questions of possible noncompliance.

Sometimes medication is the best choice. Here's how to find -- and use -- the most effective drug for you.

Presents the case of gabapentin-induced dystonia. A 72-year-old woman complained of tremors of both arms. She had a history of depression and hypertension, the latter treated with amiloride 5 mg/ day plus hydrochlorothiazide 50 mg/day. She denied use of any other medications, and had been on an adequate low-sodium diet for the past 5 years. At the time of presentation, she presented with postural and intention tremor of both arms and cephalic resting tremor without other neurologic symptoms. An electrocardiogram did not show any rhythm disorders. Diagnosed with essential tremor, she was treated with propranolol 120 mg/day. However, symptomatic bradycardia made it necessary to withdraw the drug. Gabapentin was initiated, with slow dosage escalation, to 2,100 mg/day after 7 weeks of treatment. Shortly after starting the medication, the patient developed abruptly repetitive rotatory and sustained movements of the neck, as well as proximal contractions in the arms. She stopped gabapentin on her own, with resolution of the dystonic reaction. There was no family history of dystonia. Gabapentin was restarted at a lower dose than before and was titrated to a total of 1,800 mg/day in the sixth week. Subsequently, the patient developed a recurrence of her dystonic reaction. The case described is consistent with gabapentin-induced dystonia. However, conflicting data suggests that gabapentin may be efficacious in the treatment of some types of movement disorders but in other patients may actually precipitate movement disorders. Whether the outcome is a function of dosage used, individual predisposing factors, or some combination of factors at present is not known.