Pharmacodynamic moment

Consider modafinil (Provigil) and its isomer armodafinil (Nuvigil) not as classic stimulants, but as novel stimulants or wake-promoting agents as their mechanism of action is different than the true, classical stimulants

These two wake promoters do require an intact DAT system, but it is unclear if they block this transporter, reverse the transporter, or facilitate vesicular monoamine transporter systems like the classic mixed amphetamine salts. Most likely the mechanism is of a DRI

They also may promote wakefulness by promoting downstream histaminergic activity and orexin activity

Currently, these two agents are approved for treating narcolepsy, obstructive sleep apnea (OSA) fatigue, or shift-work sleep disorder fatigue

Evidence is mounting for their successful use in bipolar depression

Two-minute tutorial

What is worse in causing escalated mania or mixed features, antidepressants or stimulants?

Recent reports suggest less risk of triggering bipolar disorder onset among stimulants and antidepressants than previously thought, particularly in adolescent patients who are thought to be prone to activation of bipolarity

Smaller controlled trials in adolescents with ADHD and bipolar disorder support the notion that stimulants may also trigger less escalation to mania than antidepressants

Should unipolar antidepressants be used in bipolar disorder?

Guidelines and data from the last few decades suggest that mania, mixed features, and rapid cycling may be induced in bipolar 1 patients when antidepressants are added to their medication regimens. Data regarding stimulant additions are relatively less well known

The TCA and MAOI antidepressants appear to cause these bipolar exacerbations more often than the SSRI class or an NDRI (bupropion[Wellbutrin])

The SNRI are suspected to be similar to the TCAs given that both classes involve dual reuptake inhibition and have similar mechanisms of action

Guidelines suggest avoiding the use of unipolar antidepressants in bipolar depression unless an adequate mood stabilizer or atypical antipsychotic is already therapeutically dosed

In the case of bipolar depression, approved treatments should be utilized first (olanzapine–fluoxetine combination [Symbyax], quetiapine [Seroquel], quetiapine [Seroquel-XR]), or lurasidone [Latuda])

However, it should be noted that these agents have more serious adverse effects (metabolic disorder, movement disorders, sedation, EPS, and possibly agranulocytosis) and require laboratory monitoring and higher healthcare utilization. These agents, when used for depressive disorders, carry the risk of increasing suicidal symptoms in those younger than 25 years

Considering that bipolar patients spend more time depressed and may accrue more cumulative disability from the depressed state, novel treatments without end organ damage risk are needed

Certain unipolar antidepressants (SSRI, NDRI) offer an option for less medically risky treatment but with minor risks of worsening the principal bipolar illness at hand. This fact is more apparent in treating bipolar II patients

Does clonazepam (Klonopin) work in bipolar mania?

It is not approved

Data are available for this intervention, as follows:

• – APA guidelines for acute manic or mixed episodes suggest that BZs may make effective adjuncts while awaiting the effects of a primary anti-manic agent to become evident

• – APA guidelines recommend combination therapy for patients inadequately controlled within 10–14 days of optimized-dose first-line treatment as another instance where BZ intervention may be warranted

Five randomized controlled studies of the BZ clonazepam for acute mania exist and were conducted in small patient populations

Meta-analysis suggests that clonazepam reduced mania scores statistically

Furthermore, there may be higher efficacy of clonazepam versus lorazepam (Ativan)

Some case studies suggest that clonazepam is efficient in reducing symptoms of acute mania even when used as monotherapy

Dosing in these trials ranged from 2–6 mg/d