Psychosis. The SGAs must be added to the regimen, working down the list as indicated in Table 2 (Pavuluri et al., 2004d, 2004e).
Persistent aggression. Switch to SGA monotherapy if mild aggression is present. In moderate to severe presentations, a combination of mood stabilizer and SGA is used (Table 1 and Table 2). Clonidine (Catapres) can be used to subdue rage attacks (Prince et al., 1996). However, children can become disinhibited or become more aroused after persistent use, although this particular observation needs to be further examined.
Treatment resistance. Chronic unremitting symptoms must be treated by: 1) alternative monotherapy; 2) at least two trials of combination regimes of mood stabilizers plus SGA; and 3) triple therapy addressing comorbid conditions.
Sleep difficulties. It is customary for the clinician to take advantage of increasing the p.m. dose of a sedating mood stabilizer. Beyond that, melatonin 1 mg to 3 mg (Smits et al., 2003), tiagabine (Gabatril) 5 mg (Gustavson et al., 1997; Mathias et al., 2001) or trazodone (Desyrel) 150 mg (Balon, 1994; Saletu-Zyhlarz et al., 2003, 2001) can be administered to establish a proper sleep routine that is critical in PBD. While these compounds are not empirically supported by research specifically on sleep disorders in PBD, they are known to be sedative, safe in pediatric populations, and to interfere minimally with rapid eye movement sleep. In subjects with abuse potential, benzodiazepines may be misused and medications such as trazodone may be effective alternatives (Rush et al., 1999).
Problem solving. While ADHD is a distinct disorder from PBD, it is not understood if the ADHD-like symptoms in PBD warrant additional treatment beyond mood stabilization. In our study, several subjects continued to show symptoms of inattention post-mood-stabilization that warranted stimulant medication (Pavuluri et al., 2004d). Stimulants are almost always given in long-acting form unless an additional after-school dose is required to sustain the benefits. Methylphenidate (Ritalin long-acting, Concerta) or mixed amphetamine salts (Adderall) are equally effective. Atomoxetine (Strattera) is an alternative treatment if stimulants have been ineffective (Pavuluri et al., 2004d). There are no data establishing safety or efficacy of atomoxetine in treating comorbid ADHD and PBD. Atomoxetine is a selective norepinephrine reuptake inhibitor with potential antidepressant effects and could theoretically trigger or exacerbate symptoms of mania.
Anxiety. Anxiety disorders, including generalized anxiety disorder and separation anxiety disorder, are relatively common, especially in bipolar I disorder. Psychotherapeutic interventions, such as cognitive-behavioral therapy (CBT), remain the first choice of treatment for comorbid PBD and anxiety disorder. The SSRIs are the only medications consistently shown to be effective in controlled trials for childhood anxiety disorders (Birmaher et al., 2003; Black and Uhde, 1994; Research Unit on Pediatric Psychopharmacology Anxiety Study Group, 2001). This treatment requires educating the family about the risk of a manic switch, and close monitoring of treatment response is necessary. Benzodiazepines (Bernstein et al., 1990; Graae et al., 1994; Simeon et al., 1992) and buspirone (BuSpar) follow as alternative choices. Risk for developing dependence needs to be considered with long-term use of benzodiazepines in adolescents. Buspirone may not be effective in all cases. Propranolol (Inderal) may be considered in cases of performance anxiety.
Adverse events. Low doses and slow titration are two fundamental principles that keep adverse events to a minimum. If problems continue, switching to an alternative medication may be necessary. Despite several antidotes for weight loss, the single most important intervention is diet and exercise. Long-acting preparations of divalproex or lithium, or taking SGAs before bed tend to decrease gastrointestinal upset. An endocrine consultation is needed to evaluate for hypothyroidism, which may or may not be related to lithium use.
Since the commencement of our algorithm project and the subsequent publication of our feasibility study (Pavuluri et al., 2004d), we have continued to update our strategies and tactics based on new information. Aripiprazole (Abilify) was added to the list of SGAs. The role of lamotrigine has been elevated. Atomoxetine was added as a second-line medication for comorbid ADHD. Clonidine has been shown to cause worsening of symptoms in a subgroup of patients with PBD, despite excellent short-term response for autonomic arousal.
