Triple reuptake inhibitors: What to expect from ‘mega-antidepressants’

By acutely blocking dopamine reuptake, triple reuptake inhibitors could have immediate effects on dopamine-related depression symptoms such as anhedonia, rather than requiring a lead-in of chronic dosing common to other antidepressant classes.¹⁶ A triple reuptake inhibitor also might:

• address a broader range of depression symptoms, compared with a single or dual reuptake inhibitor
  
• be useful for treating substance abuse if it can substitute for addictive compounds at the dopamine transporter without possessing reinforcing characteristics.
  

Because of dopamine transporter blockade, triple reuptake inhibitors may pose their own risks for reinforcing effects and abuse, as seen with cocaine and amphetamine. Imaging studies have shown, however, that the rate of dopamine transporter blockade—rather than the affinity of the drug for the transporter—is relevant to reinforcing effects.³³ Nonetheless, these medications will require evaluation for dependency characteristics that could limit their clinical use.

Side effects observed with SSRIs, such as sexual dysfunction and weight gain, can be related to a continuous, high occupancy of serotonin transporters. This effect might not occur with a triple reuptake inhibitor and the incidence of serotonin-associated side effects might be lower.¹⁴

Related resources

• Nutt DJ. The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry 2006;67(suppl 6):3-8.
  
• American College of Neuropsychopharmacology. Neuropsychopharmacology: the fifth generation of progress. www.acnp.org/Default.aspx?Page=5thGenerationChapters.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Duloxetine • Cymbalta
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Paroxetine • Paxil
  
• Pergolide • Permax
  
• Phenelzine • Nardil
  
• Pramipexole • Mirapex
  
• Reboxetine • Edronax
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Shaw and Dr. Boules report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Dr. Richelson is a consultant to Eli Lilly and Company.