When nothing works for bipolar depression - there’s hope
Bipolar depression can be uniquely difficult to treat. Many people try multiple mood stabilizers, antidepressants, talk therapy and other treatments before finding relief—if they find relief at all. For those living with treatment-resistant bipolar depression (TRBD), the emotional weight, functional impairment, and elevated suicide risk can feel unmanageable.
Over the last decade, ketamine-assisted therapy has emerged as a rapid-acting antidepressant option that may help when standard treatments fail. Research continues to evolve, but the evidence to date suggests ketamine can offer hope—if delivered carefully, with proper monitoring, and within a structured treatment plan.
What Makes Bipolar Depression So Challenging?
Unlike unipolar (major) depression, bipolar depression tends to:
Last longer
Respond less reliably to antidepressants
Carry higher rates of suicidal thinking
Be more sensitive to medication-induced mood destabilization
This makes the need for fast-acting, effective interventions even more important—while also demanding caution to avoid switching to a manic episode.
How Ketamine Works
Ketamine doesn’t operate like typical antidepressants. Instead of targeting serotonin or norepinephrine, ketamine acts primarily on the glutamate system.
Key mechanisms include:
NMDA receptor antagonism
Increased glutamate signaling through AMPA receptors
Activation of neuroplasticity pathways (BDNF, mTOR)
Synaptic regrowth, which may reverse the “stuck” depressive brain state
These processes may explain why ketamine can relieve depression within hours to days, compared to the weeks standard antidepressants require.
What the Research Shows About Ketamine for Bipolar Depression
Growing evidence supports ketamine as a promising treatment for treatment-resistant bipolar depression (TRBD):
✅ Rapid antidepressant effects
Multiple studies show significant symptom reductions within 1–3 days after infusion.
✅ 30–50% response rates
Real-world clinic data and controlled studies frequently report this range among TRBD patients—higher than many conventional options for this population.
✅ Reduction in suicidal ideation
Some studies show meaningful decreases within hours.
✅ Safety profile is cautiously encouraging
Studies report low—but not zero—rates of mania or hypomania, especially when patients remain on mood stabilizers.
Key information from recent research
A 2023 systematic review found that ketamine shows “promising therapeutic potential” for bipolar depression, with rapid symptom reduction but a need for larger trials. (1)
2024–2025 research highlights meaningful real-world benefits in TRBD patients, though methodology varies and long-term evidence is limited. (2)
Several 2024 clinical cohorts show response rates in the 30–50% range with low absolute rates of manic switching, while emphasizing the importance of mood-stabilizer co-management. (3)
How Ketamine Is Administered
1. Intravenous (IV) ketamine
Common dose: 0.5 mg/kg infused over 40 minutes
Usually delivered 1–2× weekly over 4–6 sessions
Most evidence exists for IV ketamine
4. Maintenance treatments
If patients respond, they may receive:
Periodic booster infusions
Integrated psychotherapy to prolong effects
Optimal maintenance protocols for bipolar patients are still being studied.
Benefits
Fast relief, especially important for severe or suicidal depression
Effective for many who failed multiple medications
Different mechanism from traditional antidepressants
May improve functioning and cognitive rigidity associated with bipolar depression
Many clients describe ketamine sessions as creating “mental space,” or temporarily dissolving the depressive fog that makes change feel impossible.
Risks & Considerations
1. Manic or hypomanic switch
Although uncommon and a low risk, it has been documented —especially without a mood stabilizer onboard.
2. Dissociation
Short-term, typically during treatment. Some find this very pleasant.
3. Blood pressure elevation
Clinics monitor this before, during, and after each session.
4. Long-term safety
Potential risks long-term (urinary, cognitive, dependence) are still being researched.
5. Off-label status
Ketamine (IV) is off-label for psychiatric use.
Bottom line:
Ketamine is not a first-line treatment for bipolar disorder, but for the right patient—with the right monitoring—it may be a powerful tool.
Questions to Ask Before Starting Ketamine
Is ketamine safe for my bipolar type (I or II)?
Should I be on a mood stabilizer during treatment?
What does your acute and maintenance schedule look like?
How will you handle integration therapy?
What outcomes do you typically see in bipolar patients?
How do you track safety long-term?
While ketamine is not a cure for bipolar depression, it represents one of the most promising treatment avenues for individuals who have exhausted conventional medication pathways. When integrated into a comprehensive plan—including mood stabilizers, therapy, and lifestyle support—it may offer rapid relief, renewed hope, and a path toward meaningful recovery.
If you're considering ketamine therapy in the Toronto area, Greg Rennie, a Psychotherapist who specializes in bipolar disorder, is also trained in ketamine-assisted psychotherapy and partners with a Toronto Ketamine Clinic. Ask him the critical questions listed above. With careful guidance, ketamine can be a safe and transformative part of your mental-health journey.
Sources:
Fancy F, Haikazian S, Johnson DE, et al. Ketamine for bipolar depression: an updated systematic review. Ther Adv Psychopharmacol. 2023;13:20451253231202723. doi:10.1177/20451253231202723. PubMed
Santucci MC, Ansari M, Nikayin S, Radhakrishnan R, Rhee TG, Wilkinson ST. Efficacy and safety of ketamine/esketamine in bipolar depression in a clinical setting. J Clin Psychiatry. 2024;85(4):24m15376. doi:10.4088/JCP.24m15376. PubMed
Pastuszak M, Cubała WJ, Kwaśny A. Residual depressive symptoms in treatment-resistant bipolar depression following short-term ketamine administration. Drugs Real World Outcomes. 2024;11:565-571. doi:10.1007/s40801-024-00453-y. SpringerLink
