Anxiety and Depression - Behind the papers- what's the current evidence?
Just about everyone is aware of at least someone in their personal circle who has struggled with anxiety and/or depression. More worrying is that these two conditions are set to affect more and more people over the coming decades.
What is quite sad is that our scientific understanding of these conditions still remains quite primitive. The result is that we hold a pretty limited toolbox for treating these global issues. Antidepressant drugs don't necessarily provide a “cure", and other therapies that can make the crucial difference are usually not in sufficient supply. Psychiatrists suggest staying on antidepressants for six months to a year after feeling better. However, often doctors can confuse withdrawal symptoms with a return of depression, and restart the drug. This can keep people trapped on antidepressants for life.
Psychedelics as the new promising intervention for depression and anxiety
So, with the arguable exception of Spravato (esketamine nasal spray), we have had no new treatments against depression that has developed in the last 25 years. Psychiatrists are looking for alternate approaches to support patients suffering from depressive symptoms. There is a push by a growing community of clinicians who believe psychedelic-augmented therapy may represent a revolutionary new alternative for patients with depression and anxiety that are ineffectively managed by conventional methods (1).
Academic studies have shown promising results that suggest that psychedelic-augmented therapy represent a promising paradigm for depression. However, for truly concrete data, we will have to wait for larger double blind randomised controlled clinical trials to be conducted with these substances.
Here is a simple breakdown of the evidence to date from 7 key studies designed to assess the role of administering psychedelics +/- therapy to treat individuals with anxiety/depression.
The seven key studies
x1 study with Ayuahuasca in patients with recurrent depression
x5 studies with psilocybin - 2 studies in patients with treatment resistant depression and 2 studies with patients with life threatening cancer experiencing anxiety and depression.
x1 study with LSD in patients with anxiety with advanced stage cancer
All the studies used a variety of standardised rating scales to assess the severity of anxiety and depression.
Summary of Studies
Overall, the studies described below have all shown statistical reductions in scores of depression and anxiety both immediately and up to 12 months later. What is interesting is the improvement in scores were not found in control patients which would indicate that the antidepressant and anxiolytic effects can be attributed to the psychedelic intervention.
Safety and Tolerability
Overall these studies have shown that ayahuasca, psilocybin and LSD are relatively well tolerated in humans. Reassuringly there were no significant adverse effects reported such as cases of prolonged psychosis. The most common symptoms were transient anxiety, headache and nausea. Mild but non significant increases in heart rate and blood pressure were reported in a significant number of patients but all effects resolved after the drug effects subsided.
This growing evidence that psychedelic-augmented therapy has the ability to provide acute symptom relief, i.e. within one day. This contrasts with current antidepressants, which take several weeks to work. The delayed effects from current antidepressants are linked to high levels of non-compliance and may contribute to other detrimental impacts on health. Moreover, early evidence suggests enduring symptom improvement for depression and anxiety following psychedelic-augmented therapy. Symptom relief can be sustained for several months, presenting the opportunity to use such a treatment that requires much less frequent intervention than current treatments.
Limitations to current studies
However, there are limitations to the research studies described below. Studied patient groups are small with patient sample sizes between 6-50. The outcome measures used in these studies are subjective as rely on clinicians rating patient symptoms. There is also the risk of expectancy bias which refers to the fact that the sub-conscious expectancy of the researcher to the likely outcome of the experiment acts as a self-fulfilling prophecy, biasing the results in the direction of the expectation.
So what is next with research into this space?
Before widespread use can be contemplated, a number of questions to be answered by academics as well as through regulated clinical trials. Areas that still need further investigation include:
Validating these promising results on a larger scale
Conducting trials that are longer in duration
Testing the long term safety and efficacy of the drug
Identifying which patient groups/ profiles are most likely to respond
What are the optimum dosing for treatment with the different compounds
Which use case in the clinical setting is most appropriate for psychedelic therapy e.g. use in patients with treatment resistant conditions, or used in patients as first line.
Risks of using psychedelics in patients on antidepressants
Understanding the contribution of psychotherapy - how significant is it or is it just supportive
What is the likely cost to receive this treatment if it is approved
Summary of studies [3]
Before reading the study summaries, here are a few key definitions used to describe the trials.
Definitions
Open label: the situation when both the researcher and the participant in a research study know the treatment the participant is receiving. Open-label is the opposite of double-blind
Double blind study: neither the researcher nor the participant knows what treatment the participant is receiving ( gold standard)
Randomised control: subjects are randomly assigned to one of two groups: one (the experimental group) receiving the intervention that is being tested, and the other (the comparison group or control) receiving an alternative (conventional)
(Considered to provide the most reliable evidence on the effectiveness of interventions because the processes used minimise the risk of confounding factors influencing the results.)
Crossover study: Study participants receive each treatment ( including placebo) in a random order. With this type of study, every patient serves as his or her own control.
Placebo control: using an inactive drug/ treatment in the study. Used to help researchers understand what effect a new drug/ treatment might have on a particular condition by compare the effects of the drug and the placebo on the people in the study.
Validated depression rating scales: scales using descriptive words and phrases that indicate the severity of depression by scoring a person's behaviour. Validated scales that are completed by researchers/clinicians ( e.g. HAD and MADRS) , self-reported by patients ( e.g. BDI, PHQ-9).
Major Depressive Disorder (MDD) characterised by two weeks of low mood, associated with low self esteem, lost interest in normally enjoyable activities, low energy.
Treatment Resistant Depression: individuals with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time.
Adjustment syndrome: group of symptoms, such as stress, feeling sad or hopeless, and physical symptoms that can occur after you go through a stressful life event.
Phase II trial: Performed on larger groups (100–300) and are designed to assess how well the drug works on patient target group and find the optimum dose at which the drug works with minimal side-effects.
Phase III trial: These are large trials (300-3000) to compare the drug to standard therapies for the disease or condition being studied, and to evaluate the overall risks and benefits of the drug and its value in clinical practice. If proved satisfactory after Phase III, a regulatory submission for market approval can be submitted to the regulators.
Psilocybin for treatment resistant depression
Study 1: Carhart-Harris et al (2016) [4]
Design: Open Label Trial with 12 patients with moderate to severe TRD Each patient received 2 doses of psilocybin one week apart ( a low safety dose and subsequent higher dose) alongside psychological support before, during & after each session.
Outcome: Decrease from baseline in depression scores at week 1 and month 3 post treatment. At month 3, more than half participants still continued to have effectively treated from their depression and a significant number maintained significant reductions in their anxiety.
Study 2: Carhart-Harris et al (2018) [5]
Design: 6 month follow up with 12 patients from previous study + further 8 male participants. Outcome: Sustained antidepressant and anxiolytic response on 8 patients for 6 months post treatment.
Psilocybin for cancer related psychosocial distress.
Two randomised placebo controlled studies at John Hopkins and NYU were conducted to assess the effects of psilocybin on patients with life threatening cancer.
Outcome: No significant adverse events. Remarkable efficacy unprecedented for any currently available conventional therapy for CRPD.
Study 3 - John Hopkins University - Griffiths et al.2016 [6]
Design: 51 patients with anxiety and depression in patients with life threatening cancer 2 sessions ( high dose vs placebo low dose psilocybin)
Outcome: Significant anti-depressant and anxiolytic effects with more than 80% of patients reporting sustained improvement in symptoms at 6 months. Those with strong mystical experience had great therapeutic impact.
Study 4 - Ross et al. 2016 [7]
Design: 29 patients enrolled with cancer and diagnosis of anxiety or adjustment syndrome. Patients randomly assigned to receive either a niacin placebo+ psychotherapy or single dose of psilocybin + psychotherapy.
Outcomes: Patients receiving psilocybin + therapy showed immediate and sustained reductions in anxiety and depression symptoms that were not seen in those taking niacin placebo. 60-80% showed sustained reduction in symptoms at 6.5 months .
Study 5 - Grob et all [8]
Design: Comparing psilocybin and placebo ( niacin) to 12 patients with advanced stage cancer with known anxiety related to their advanced stage cancer using a double blind, randomised, crossover trial
Outcome: Significant reduction in anxiety and depression at 1 and 3 months
LSD assisted therapy for anxiety associated with life threatening disease
Study 6 - Gasser et al. [9]
Design: 12 patients with anxiety related to diagnosis of life threatening disease 200 ug LSD vs 20ug active placebo with two drug-free psychotherapy sessions and two LSD-assisted psychotherapy sessions
Outcome: No serious adverse effects. Positive reduction in anxiety at 2 and at 12 months after treatment. Sustained reduction in anxiety of 7/9 participants No long lasting negative effects reported
Ayuhuasca for depression
Study 7- Osorio et al. 2015 [10]
Design: Open Label study with a single dose of Ayuhuasca in 6 patients with recurrent MDD. Outcome: Up to 82% reduction in depression scores from baseline at day 1, 7 and 21 after taking ayahuasca. Specific depression related symptoms with greatest reduction: depressed mood, feelings of guilt and suicidal ideation.
Other active trials
The above studies describe academic studies conducted in this space. However, there are a number of not-for-profit and for-profit organisations now pushing the advancement of psychedelic therapy for clinical use. Regulatory approval has been passed to conduct clinical trials using psilocybin, LSD and MDMA.
Current active studies in depression and anxiety: Phase II clinical trial (active)- psilocybin on Treatment Resistant Depression ( Compass) Phase II clinical trial (active) - psilocybin on Depression ( Usona)
References
(1) Lemay, K., Wilson, K., 2008. Treatment of existential distress in life threatening illness: a review of manualized interventions. Clin. Psychol. Rev. 28 (3), 472–493.
(2) Spiegel, D., 2015. Existential psychotherapy for patients with advanced cancer: facing the future and the past. J. Clin. Oncol. 33 (24), 2713–2714.
(3) Muttoni, S., Ardissino, M., & John, C. (2019). Classical psychedelics for the treatment of depression and anxiety: a systematic review. Journal of Affective Disorders. doi:10.1016/j.jad.2019.07.076
(4) Carhart-Harris, R.L., Bolstridge, M., Rucker, J., Day, C.M., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J.A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V.H. & Nutt, D.J. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry (2016)
(5) Carhart-Harris, R.L., Bolstridge, M., Day, C.M.J., Rucker, J., Watts, R., Erritzoe, D.E., et al., 2018. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl.) 235 (2), 399–408.
(6) Griffiths, R.R., Johnson, M.W., Carducci, M.A., Umbricht, A., Richards, W.A., Richards, B.D., Cosimano, M.P. & Klinedinst, M.A. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology (In press)
(7) Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S.E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P. & Schmidt, B.L. Rapid and Sustained Symptom Reduction Following Psilocybin Treatment for Anxiety and Depression in Patients with Life-Threatening Cancer: A Randomized Controlled Trial. J Psychopharmacol, in press (2016).
(8) Grob, C.S., Danforth, A.L., Chopra, G.S., Hagerty, M., McKay, C.R., Halberstadt, A.L. & Greer, G.R. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch. Gen. Psychiatry, 68(1), 71-78 (2011).
(9) Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., 2014. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J. Nerv. Ment. Dis. 202 (7), 513–520. Available from.
(10) Osório, F.L., Sanches, R.F., Macedo, L.R., Santos, R.G., Maia-de-Oliveira, J.P., WichertAna, L., et al., 2015. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Revista Brasileira de Psiquiatria 37 (1), 13–20.