W1 T3 P3

• New treatments for mood disorders are in development.

Ketamine

• Ketamine is a dissociative anaesthetic.
• Ketamine acts as an antagonist on NMDA receptors.
• Ketamine was recently licensed in the UK for depression.
• It has a new therapeutic mechanism of action.
• Ketamine has a rapid onset of therapeutic effect.
• Ketamine is effective for suicidality.
• Ketamine can be administered at lower doses.
• High effect sizes are seen for reducing depressive symptoms in bipolar and unipolar depression.
• The antidepressant effect is rapid
• A single dose can keep symptoms reduced for up to two weeks.
• It is challenging to maintain the effects of ketamine long term.
• Concerns exist about the potential for abuse and dependence.
• Adverse health effects with long-term use are a concern.
• Poor reporting of adverse effects in trials is noted.
• Adequate control arms are lacking in studies.
• Participants can often tell if they received ketamine or a placebo.
• There are few long-term studies currently.

Psychedelic Compounds

• Psychedelic compounds may treat unipolar depression.
• They represent another rapid-acting intervention.
• Psilocybin has anecdotal evidence of mood-lifting effects dating back centuries.
• Psilocybin has a Phase I trial indicating broad safety and tolerability in healthy people.
• There is a randomised controlled trial suggesting antidepressant efficacy in people with major depressive disorder.
• Several ongoing trials are researching psilocybin in people with unipolar mood illnesses.
• Ayahuasca and N-dimethyltryptamine (DMT) are being looked at.
• DMT has been subject to uncontrolled studies, but now has one controlled Phase I trial ongoing in healthy people.
• Psilocybin's rapid-acting antidepressant effect may last longer than ketamine.
• There are fewer concerns over dependence and long-term adverse effects with psilocybin.
• The research pathway for psilocybin is still early.
• There is more uncertainty with psilocybin, particularly for people with bipolar disorders.
• Challenges around blinding and long-term effects are similar to ketamine.
• Self-selecting samples may be an issue.
• People who have previously benefited from these agents are more likely to volunteer for trials.
• Psychotherapeutic integration is thought to be needed during and after a psychedelic experience to help people benefit affectively.
• This may be costly.

Neuromodulation

• These interventions stimulate the brain to change activity and improve symptoms.
• Repetitive transcranial magnetic stimulation (TMS) is well-evidenced and licensed for depression in the UK.
• TMS delivers electromagnetic pulses to specific brain regions.
• There are no adverse long-term effects known about with TMS.
• TMS is considered easy and acceptable to patients as it does not require anesthesia.
• Response rates with TMS are not outstanding, with fewer than half of patients responding.
• Only about one quarter of patients fully remit from depression with TMS.
• Issues exist around the longevity of antidepressant effects and blinding in the trials for TMS.
• Transcranial direct current stimulation (TDCS) involves a low amplitude electrical current applied directly through electrodes on the head.
• TDCS targets brain activity near the surface.
• UK guidelines for depression contain some guidance about TDCS, but this is limited.
• Deep brain stimulation (DBS) and vagus nerve stimulation (VNS) are not provided in the UK.
• Electroconvulsive therapy is a source of great controversy.
• Electroconvulsive therapy is considered one of the most effective therapies for mood disorders.
• It has response rates up to 80%.

Other Treatments

• Anti-inflammatory medications are being trialled to treat mood symptoms.
• These medications also focus on ameliorating different biological abnormalities associated with these illnesses.
• They have been observed to improve depressed mood in groups of people with inflammatory illnesses.
• These treatments help treat both depression and mania.
• Larger new trials haven't shown particular benefits with anti-inflammatory medications for depression.
• Cognitive and functional enhancement interventions are being heralded for people with cognitive impairment and bipolar disorders.
• Some of these are psychosocial, like cognitive remediation therapy or functional remediation therapy.
• Some are pharmacological, including modafinil and lurasidone.
• Interpersonal and social rhythm therapy or IPSRT focuses on stabilising circadian rhythms for overall affective benefits.
• IPSRT is mainly for people with bipolar disorders.
• There appears a stronger circadian element to bipolar disorders, linked with depressive and manic relapses.
• IPSRT targets particular elements not considered central to the illness, like circadian routine and interpersonal difficulties.
• Suicide-focused interventions are mainly from therapies already used in people with affective disorders.
• These include lithium, electroconvulsive therapy, ketamine, and dialectical behavioural therapy.
• The focus on suicide is a good example of a translational focus of the RDOC approach.
• Thinking about people experiencing a particular difficulty and treating based on that rather than treating people based simply on the diagnosis that they have.

Ketamine, a dissociative anaesthetic and NMDA receptor antagonist recently licensed in the UK for depression, offers a novel therapeutic mechanism with rapid antidepressant effects, including reduced suicidality. While effective for bipolar and unipolar depression, maintaining long-term benefits is challenging, and concerns exist regarding abuse, dependence, and adverse effects.