Novel rapidly acting drugs to treat depression and other psychiatric disorders: Buprenorphine

by J.E - Newcastle University

Opioids were widely used to treat depression from 1850-1956. Once current standard antidepressants (such as tricyclic antidepressants and monoamine oxidase inhibitors: See document on antidepressants) were identified, these replaced the use of opioids, driven by concerns over opioid abuse potential, dependence, and dangers of overdose[1, 2]. The opioid system may be involved in the regulation of mood. Modifying central opioid receptors may be a novel approach to treating depressive disorders that are unresponsive to conventional treatments [2, 3].

Buprenorphine acts on certain opioid receptors. However, in addition, Buprenorphine interacts with the serotonergic systems and the Hypothalamic Pituitary Adrenal Axis (HPA Axis) both of which are involved in mood regulation and depression. This has led to it being examined as a treatment for depression.

Buprenorphine is a class C, controlled drug. Possession is illegal without a prescription and carries a maximum sentence of 2 years imprisonment and a fine. It is used in higher doses in patients with opioid use disorder and can also be used to treat pain syndromes.

Ahmadi 2018[4], Showed a single administration of a high dose of buprenorphine in patients with comorbid opioid dependence -reduced suicidal ideation. Being a single dose reduces concerns regarding compliance, dependence, and abuse. During the study – no illicit opioid use was detected.

Lower doses can be given more regularly. A research study was carried out in 2016 on non-opioid dependent severely depressed patients [5].

In this study 0.1-0.2mg a day for a week were administered sublingually and once a week the daily dose could be increased by 0.1-0.2mg increments to a maximum dose of 0.8mg. The study lasted 4 weeks. Improvements in depressive symptoms were seen within the first week of starting 0.2mg sublingual dose of buprenorphine. The effect was sustained whilst taking this medication; but when discontinued- depressive symptoms returned. Longer term (i.e. more than 4 weeks) low dose buprenorphine may be required for sustained effects.

In patients with depression, a high dose of buprenorphine used as a single one off dose in opioid dependent patients may be efficacious in the treatment of suicidal tendencies (Ahmadi 2017). Similarly, a time limited short-term use of low dose buprenorphine is associated with reduced suicidal ideation in severely suicidal patients without substance abuse [5, 6].

There have been a number of additional studies:

• Emrich [7] reported the antidepressant effect of buprenorphine in a group of 10 depressed patients. 50% responded (with at least a 50% decrease in their depressive symptoms).
• Bodkin [8] showed that buprenorphine was effective in the treatment of Difficult -to -Treat Depression (link to article on DTD) with non-psychotic symptoms.
• Nyhuis[9] showed the effectiveness of buprenorphine to treat depression not responding to conventional antidepressants and ECT. Five of six patients with major depressive disorder showed complete remission (being essentially symptom free) on taking sublingual buprenorphine 0.8-2mg once a day for a week.
• Stanciu [2] showed that when given an adequate dose of buprenorphine- most patients experienced benefits within 3 hours. Effects were seen in 10-20% of patients. The effects of buprenorphine on Difficult-to-treat Depression are striking. Most improvement was seen within 1 week- unlike the pattern of slow steady improvement with conventional antidepressants.

Aside from depression, buprenorphine has also been investigated as a possible treatment for obsessive-compulsive disorder (OCD). Both psychopharmacology and psychotherapeutic interventions are used to treat OCD. Pharmacological treatment is usually with an antidepressant, specifically an SSRI or the tricyclic antidepressant Clomipramine. In patients with difficult-to-treat OCD, Buprenorphine when added to SSRIs or clomipramine has been shown to reduce OCD symptoms when compared to a placebo [10]

Side effects of buprenorphine are seen in 10-20% of patients and include nausea, vomiting, and sedation.

Buprenorphine (BUP) is a partial μ-opioid receptor agonist and κ-opioid receptor antagonist Samidorphan (SAM) [11]has been demonstrated to function as a μ-opioid antagonist. It has been suggested that SAM in combination with BUP may stop the abuse and dependence potential of BUP, while preserving its antidepressant effects. This combination (BUP/SAM 2mg/2mg) has been compared with a placebo in patients with difficult to treat depression [12]. 2mg/2mg Buprenorphine/Samidorphan consistently reduced depression symptomology compared to the placebo. This combination was well tolerated. Side effects that occurred in some patients included: nausea, constipation, dizziness, vomiting, drowsiness, fatigue, and sedation. There was minimal evidence of abuse. This positive finding has led to research on drugs that act just on kappa opioid receptors, which in theory should be free of risk of addiction eg Aticaprant.

CONCLUSION

Currently, the only rapid-acting antidepressant that is licensed for use in the UK is intranasal esketamine. However, there are a number of other, different, drugs, such as buprenorphine also being investigated as possible treatments for depression. Many of these may have abuse potential. It is important that they are researched in well managed, professionally conducted, studies avoiding patients becoming vulnerable to unproven treatment from unregulated practitioners. It is essential to establish and maintain strong safety parameters when using novel rapidly acting drugs. It may be possible for special clinics to be established to treat very unwell patients in a comfortable, safe environment with specialist staff and experienced psychiatrists who are familiar with the effects of hallucinogenic agents and have emergency “rescue drugs” should the patient become distressed. Research is ongoing and it is hoped that it will provide relief to patients who are suicidal or severely depressed, who have failed to respond to conventional therapies.

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