What about the risk of triggering mania?

First of all I should know the doses of all drugs he takes daily and the serum lithium assay. Anyhow I would never give a bipolar patient an amphetamine. The antidepressant drugs themselves should be used with caution. In principle in this particular case I would try to add paroxetine 10 mg /day after breakfast, increasing to 20 mg /day after 1 week if needed.

Anthony G Gordon Excellent observation. This risk is very high and it's hazardous as well especially in bipolar I patients

What about betablocker interference? It should be seriously reconsidered. A known suicidal aspect. In this case, better no additional medication anyway.

Thank you so much Anthony G Gordon Francesco Lusciano Eberhard J Wormer Moses P Moorthy

• McElroy SL et al. Adjunctive lisdexamfetamine in bipolar depression: a preliminary randomized, placebo-controlled trial. Int Clin Psychopharmacol. 2015;30(1):6–13.
• McIntyre RS et al. The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder. Hum Psychopharmacol. 2013;28(5):421–7.

According to those two studies: LDX is superior to placebo in reducing self reported depressive symptoms, daytime sleepiness, and fatigue. They also detected statistically significant tendency of LDX to globally improve the severity of overall depressive and bipolar symptoms. The active drug resulted well tolerated, not inducing/ worsening suicidality or hypomania/mania. Only one out of 25 patients was ruled out from the study for misuse of the drug.

Adjunctive flexible doses of LDX in stabilized ADHD-BD patients determined significant reduction both in ADHD and residual depressive symptoms, improved the global quality of life, and were not associated with (hypo)manic switches and/or BD destabilization, at least in a short-term period.

Hi Hani,

Thanks for those references. McElroy et al. is fairly positive, but the sample size is very small.

Article Adjunctive lisdexamfetamine in bipolar depression: A prelimi...

Ditto, McIntyre et al.

Article The effect of lisdexamfetamine dimesylate on body weight, me...

The major concerns around prescribing psychostimulants are

1) the possibility of increasing the risk of mania (as Anthony Gordon mentioned) or of psychosis, and also

2) the risk of non-medical use and/or diversion.

The product information for Vyvanse (lysdexamfetamine) and for dexamphetamine (D-amphetamine) both advise;

"The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate. The mechanism of interaction is unknown. Clinicians prescribing the combination should be aware of this potential interaction."

Concurrent lithium appears to reduce some of the stimulating effects of amphetamine type stimulants, eg;

Article Does Lithium Block the Effects of Amphetamine? A Report of Three Cases

Article Lithium and valproate attenuate dextroamphetamine-induced ch...

Lithium also appears to be neuroprotective against amphetamine toxicity;

Article Lithium protects against methamphetamine-induced neurotoxici...

I tend to agree with Moses and Francesco, in that psychostimulants should typically be avoided in cases with any serious risk of provoking manic or psychotic episodes, however I'm sure there is a role for cautious use in such cases when the patient does not respond well to more conventional treatment options. There are risks associated with any prescribed medication, but of course there are also serious risks associated with unresolved clinical depression.

While there are cautions/concerns with prescription of any potent psychostimulant, lisdexamfetamine has some definite advantages over traditional amphetamine type stimulants. It is a prodrug, and has no CNS activity until it has broken down via enzyme hydrolysis in the bloodstream into L-lysine and D-amphetamine.

This means the onset of action is considerably slower and gentler, which may make it less likely to provoke an acute espisode of mania, and which definitely makes it less rewarding that oral dexamphetamine. More importantly in terms of the potential for misuse or diversion, it is much less likely to be misused via insufflation or injection. It is not uncommon for people to crush dexamphetamine pills and 'snort' or inject the resulting powder, giving an immediate 'rush' effect and also resulting in a much higher dose reaching the brain (by avoiding first pass liver metabolism). By contrast, because it must circulate in the blood stream for 60 to 90 minutes before it breaks down, using lisdexamfetamine via insufflation or injection is no more rewarding than taking it orally. It takes about 5 hours to reach peak levels regardless of means of administration...

Article Intranasal versus Oral Administration of Lisdexamfetamine Dimesylate

I hope this is useful?

Regards,

Paul.

Thank you Paul Dessauer for sharing those articles, they are really helpful.

Dear Dr Guda,

You might consider bupropion retard in a starting dose of 150 mg in the morning, increasing the dose to 300 mg after a few weeks if necessary.

Kind regards,

Prof. Frederik A. de Wolff

Leiden University Medical Centre, The Netherlands

Thanks Dr Frederik A. de Wolff , Can you please give me the rational behind your decision?

Hi again Hani Guda

Brupropion does appear to be safe and effective in treating depression associated with bipolar disorder, typically with a lower side effect profile than many other antidepressants.

Article 15 Years of Clinical Experience With Bupropion HCl: From Bup...

Article Bupropion: a systematic review and meta-analysis of effectiv...

The risk of inducing mania is probably no greater with bruprorion (in doses lower than the recommended maximum, 450mg/day) than with other antidepressants.

Article Significant Treatment Effect of Bupropion in Patients With B...

G'day Prof Frederik A. de Wolff I hope you are well.

My understanding is that both lithium and brupropion can lower seizure threshold in patients with underlying vulnerabilities or in toxic doses- are there any concerns around prescribing bruproprion in conjunction with lithium?

Paul.

Dear Dr Guda, my apologies for the delay in answering your request. The rationale of considering bupropion is that it is an antidepressant with CNS-stimulating effect, chemically related to amphetamine and a noradrenaline/dopamine reuptake inhibitor. Therefore it is preferably taken in the morning to prevent insomnia. The major side effect is that it may induce convulsions in patients with a history of epileptic insults, but this is dose-dependent and does not usually occur at 150 or 300 mg/day.

Bupropion should not be combined with other drugs that interact with Cytochrome P450-2D6 such as betablockers.

An additional advantage is that it does hardly if ever induces suicidal thoughts as the SSRI’s in the onset period of therapy.

If a stimulant is appropriate, methylphenidate is the preferred class of stimulant to use in treatment-resistant depression in bipolar patients, preferably if they are on lithium as a mood-stabilizer. Here's some evidence to consider:

#1 There is a lower rate of switching to mania when compared to amphetamine class stimulants. . .

Article The Risk of Treatment-Emergent Mania With Methylphenidate in...

. . . and methylphenidate may even be a potential treatment for mania

Article Methylphenidate in mania project (MEMAP): Study protocol of ...

#2 There is a potential neuroprotective effect of methylphenidate.

Article The effect of methylphenidate intake on brain structure in a...

#3 There is significant co-morbidity of symptoms between adult-ADHD and bipolar II, both in their epidemiology, symptom clusters and genetics.

Article Moving towards causality in attention-deficit hyperactivity ...

#4 There is evidence that chronic lithium administration specifically attenuates the abuse potential of stimulants as a class by undermining over-reward signalling in the nucleus accumbens associated with stimulant-abuse (always a concern with any stimulant and also in any bipolar patient) . . .

Article Chronic Lithium Treatment Rectifies Maladaptive Dopamine Rel...

... and lithium appears to attenuate stimulant-induced impulsive behaviour better than valproate.

Article Lithium, but not Valproate, Reduces Impulsive Choice in the ...

Thanks Bryan Hopping for your contribution.

I think, options to deploy include-

1) minimize anti-cognitive drugs if used- e.g. benzos, anticholinergics

2) Modafinil (Provigil)- a wakeful promoting agent is appealing given data supporting use in bipolar depression and mitigating metabolic syndrome

3) Wellbutrin can be used with lower rates of manic-shifts

4) Omega-3 can be an alternative helping both bipolar depression and cognition

5) Donepezil- might help both

6) Pramipexol- a dopaminergic agent can help both

7) If tight mood stabilization is ensured, low dose methylphenidate can be cautiously trialled

Regards

Thanks Dr. Ahmed Naguy , I guess modafinil and low-dose methylphenidate could be good options.