The promise of an antidepressant that lifts depression in 2 hours: CNS drugs: 2012 (3)

13.11.2012

Psycho pharmacology is going through a worrying period. Many research pipelines are reported to be running dry. All,  except one or two, antidepressants we have still target the monoamine systems that were identified 50 yrs ago.Reports indicate that many companies have reduced or eliminated R&D  investment in this area, others have focused on safe areas like triple reuptake inhibitors or on modifying existing preparations.

One interesting development is that of Ketamine’s role as a possible antidepressant.

Ketamine ( NMDA receptor antagonist) is used as a short acting anaesthetic agent since 1960s.Surgical anaesthesia is produced in doses of 1-3 mg/kg. NMDA receptor is one of the three ionotropic receptor classes of Glutamate, the major excitatory neurotransmitter in the brain.Ketamine’s main metabolite  norketamine is an active substance. Ketamine has affinity to other receptors at anaesthetic dose eg. opioid receptors, it  can inhibit monoamine transport, and can stimulate D2 receptors. Ketamine can be given through multiple routes (IM, IV, oral, intranasal , subcutaneous etc).Ketamine is useful in short term management of refractory pain conditions.

Ketamine in Depression: Evidence

1.Yale University team first described the rapid antidepressant effect after single iv infusion in 8 patients. (0.5mg/kg over 40 minutes)  50% of patients had their Hamilton scores halved at 72 hrs. However, the severity returned with in 1 week. Mood lift was not part of the transient high or dissociation that could happen with Ketamine. (Berman et al ,2000)

2.NIMH study. RCT. 17 treatment resistant depression (TRD) patients. Rapid mood lift in 110 minutes. At 24 hrs, 70% response and 30% remission. Half retained the benefit for 72 hrs. One third maintained benefit for 1 week. 2 patients remained depression free for 2 weeks.(Zarate Jr et al, 2006)

3.Mount Sinai University study: 26 patients. Single dose of Lamotrigine 300mg pre treatment ( to reduce pre synaptic glutamate release, as it was thought that this will reduce the neuro psychiatric complications of Ketamine). After Ketamine infusion, glutamate release inhibitor Riluzole was given to see whether this will sustain the mood lift, in a 4 week RCT with placebo. Lamotrigine did not have any effect on psychotomimetic effects. Riluzole did not sustain the mood lift. Ketamine as before lifted mood at 72 hrs. (Mathew et al 2010)

4.NIMH study: Patients non responsive to ECT responded to ECT with IV Ketamine infusion.(Ibrahim et al  2011)

5. Repeated dose strategy: Mount Sinai study: repeated dose iv Ketamine  for 2 weeks in TRD patients who have failed to a mean of 8 antidepressants in the past. Those who responded with single iv dose was given 3/week infusions. 9/10 responded after first infusion.All nine continued their response for 2 weeks.Relapse occurred on average 19 days after last iv .( patients were not on anti deps). Relapse started from day 6, some only happened at 3 months. only 3 patients had mild dissociative effects. (Rot M et al 2010)

6.Refractory bipolar depression- small case series with IM Ketamine: higher dose produced greater effect.(Glue et al 2011)

7. A post hoc analysis of Mount Sinai study showed that iv Ketamine was associated with rapid reductions in suicidal ideas in the first 24 hrs after infusion. (Price et al 2009)

8.NIMH study has also shown acute anti suicidal effect in 33 TRD patients ( Diaz Granados, 2010).

9. Emergency room study in 14 depressed suicidal patients: iv Ketamine  (0.2 mg/kg)- improved suicidal ideation .(Larkin et al 2011).

Adverse effects:

1.Iv Ketamine can have transient cognitive effects. No residual effects reported after 72 hrs. Little information regarding effect on cognition after chronic use. Higher dose ( 1g, 4 times / week among drug users have produced impaired cognition). effects are thought to be reversible with abstinence.

2.Abuse potential is another important  worry with Ketamine

3. Psychotomimetic effects.

Conclusions:

This is a promising area.Trials are ongoing in different parts of the world.Research, though exciting , is still in its infancy. One day, antidepressants might work like analgesics. ie immediate effect and in majority of cases, remission with in weeks!

Summary of the article: Ketamine for treatment resistant Unipolar depression: Current evidence. Mathew et al. CNS drugs. 26 (3) 189-204: 2012

If you are interested in the synaptic mechanisms underlying the rapid antidepressant action see the review in Am jl psych by Kavalali and Monteggia (Am J Psychiatry 2012; 169:1150–1156).

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