Summary
Highlights
Dr. Jan Fawcett begins by acknowledging the recent loss of Robin Williams to depression, highlighting the severe suicide risk associated with treatment-resistant depression. He defines 'failed remission' and 'high relapse rates' in mood disorders, citing the STAR*D study which showed that even after four steps of treatment, only 67% achieved remission, with significant relapse rates over time. He emphasizes that current treatments for depression are not as effective as desired, particularly for treatment-resistant cases.
Dr. Fawcett explains that bipolar depression treatment can be even more challenging, with antidepressants showing limited efficacy. He mentions the surprisingly high response rate of quetiapine (an antipsychotic) in bipolar depression and the groundbreaking, albeit short-lived, effects of ketamine in severe suicidal ideation. He introduces modafinil and highlights the promising results of pramipexole in bipolar depression studies, with an impressive number needed to treat (NNT) of close to two in small studies, comparing it favorably to ECT.
Dr. Fawcett elaborates on dopaminergic medications, which increase brain dopamine function. He connects dopamine to motor movement, motivation, and the pursuit of happiness. He lists various dopaminergic drugs: bupropion (Wellbutrin), aripiprazole (Abilify), modafinil (Provigil), stimulants like dextroamphetamine, and pramipexole. He explains that pramipexole, originally for Parkinson's, increases dopamine tone and regenerates dopamine cells, improving both motor symptoms and mood. He notes that pramipexole is off-patent and underutilized in psychiatry.
Treatment resistance is defined as the failure to respond or remit after adequately received treatments. He highlights the common failure of SSRIs, SNRIs, tricyclics, and even multiple courses of ECT. Dr. Fawcett then walks through several detailed case studies of chronically treatment-resistant patients who found remission with dopaminergic treatments, specifically MAOIs and pramipexole, after failing numerous other medications and even ECT. These cases illustrate the persistence required in finding effective treatment.
Dr. Fawcett discusses anhedonia, defined as a marked decrease in interest or pleasure, as a key symptom related to dopamine depletion. He uses the analogy of Dr. Treadway's rats, who stopped seeking rewarding food when their dopamine gene was knocked out, to illustrate how dopamine drives the 'decisional anhedonia'—the motivation to exert effort for positive reinforcement. He humorously connects this concept to breaching humpback whales, suggesting their effort is fueled by dopamine-driven pleasure.
Dr. Fawcett shares his clinical experience with pramipexole (PPX). He notes that dose tolerance and requirement increase with age, opposite to most drugs, possibly due to age-related dopamine neuron loss. He advises rapid dose increases to achieve response, while managing side effects like nausea and sleepiness, which often remit within a week. He suggests administering the full dose at night to minimize side effects and mentions that the required dose is highly variable. He also notes a possibility of reduced dopamine tone needed over time as brains normalize.
Dr. Fawcett addresses the side effects of pramipexole, including increased compulsive behaviors and pathological gambling primarily observed in Parkinson's patients. He also discusses dopamine withdrawal syndrome upon sudden discontinuation. He advocates for more widespread use of MAOIs, which also increase dopamine, serotonin, and norepinephrine, arguing that their side effects (like dietary restrictions) are often exaggerated. He concludes by emphasizing the need for more dopaminergic medications in treatment-resistant depression and strongly advises seeking expert consultation for these complex cases.
In the Q&A, Dr. Fawcett advises desperate parents of adult children with treatment-resistant depression to seek consultation from leading psychopharmacologists at university medical centers. He explains that even if a doctor doesn't typically prescribe PPX, they might consider it upon suggestion. Regarding suicide risk, he notes that while antidepressants can increase suicidal ideation or attempts in those under 25, there's no evidence of increased suicides. Long-term medication adherence (over 6 months) has been shown to reduce suicide risk in highly suicidal patients.
Addressing bipolar depression, Dr. Fawcett explains it's recognized as distinct from unipolar depression, and mood stabilization is crucial before antidepressant use to prevent mood cycling. He suggests that conventional antidepressants may be less effective in bipolar depression, making alternative treatments like pramipexole or MAOIs important. He concludes by highlighting that 'depression' is likely an umbrella term for many different illnesses, and future research will lead to more specific, effective treatments based on underlying mechanisms, emphasizing the mantra: 'never give up.'