Neurobiological Effects of Psilocybin in Treatment Resistant Bipolar Depression

This study is an open-label, single-arm, proof-of-concept study, wherein treatment resistant bipolar depression (TRBD) participants will receive one 25 mg dose of oral psilocybin accompanied by preparatory, monitoring, and integration psychotherapy sessions (psilocybin-assisted psychotherapy, or PAP). Using fMRI (functional magnetic resonance imaging), the findings of this study will provide data on the neurobiological mechanism of psilocybin in TRBD.

The primary objective is to understand the dynamic role of amygdala activity by evaluating the neurobiological effects of a single psychedelic dose (25 mg) of oral psilocybin in individuals with a moderate to severe major depressive episode and a primary diagnosis of Bipolar II Disorder, with 2 or more failed treatment trials (i.e., treatment resistant bipolar depression \[TRBD\]). Neurobiological effects will be determined by evaluating the association between post-treatment right amygdala activity during the facial affect task (determined by fMRI one day after the psilocybin dose) and antidepressant effects (determined by changes in the Montgomery-Åsberg Depression Rating Scale \[MADRS\] scores over time, during the one-week period post-psilocybin dose). This is a single-arm, open-label clinical trial wherein all participants will receive the same study intervention.

Hypothesis: Increased right amygdala activity on fMRI with emotional stimuli one day after psilocybin treatment will be associated with greater antidepressant effects in the one-week period post-treatment in individuals with TRBD.

Individuals with bipolar disorder (BD) spend a third of their lives in the midst of a depressive episode. BD is a severe and persistent mental illness with a lifetime prevalence of 2-3%. Bipolar depression remains a significant treatment challenge, with a paucity of evidence-based treatments. Only four pharmacological treatments for acute bipolar depression (cariprazine, olanzapine-fluoxetine combination, quetiapine, and lurasidone) are approved by the US Food and Drug Administration (FDA). Other medications often used for the treatment of BD are those primarily used to treat mania or psychosis (i.e., lithium; antipsychotics) or major depressive disorder (MDD) (i.e., antidepressants). Lamotrigine, which is recommended by international guidelines as a maintenance treatment for BD to prevent depressive recurrence, has limited efficacy for acute BD. Current medication options are also limited by adverse effects, including renal and thyroid impairment with long-term lithium therapy and weight gain and metabolic abnormalities with atypical antipsychotics. Furthermore, treatment outcomes remain poor, particularly for depressive episodes, with over one-third of patients failing to respond to two or more first-line treatments. Hence, there is a clear need for novel and efficacious treatments for BD. However, there is a limited understanding of the neurobiology of BD, which poses as a major barrier to identifying truly innovative treatments.

Psilocybin is a chemical compound that naturally occurs in certain species of mushrooms, (for example, in the psilocybe genus, among others). It belongs to a class of drugs referred to as "psychedelics". Psilocybin is a tryptamine which is chemically similar to the neurotransmitter, serotonin, and the essential amino acid, tryptophan. It is considered a 5-hydroxytrptamineric (serotonergic) psychedelic along with other similar drugs such as dimethyltryptamine (DMT) and lysergic acid dieythamide (LSD). Psilocybin is a product for the pharmacologically active ingredient psilocin, which readily crosses the blood-brain barrier and acts as a potential partial agonist at serotonin 5HT2A and 5HT2c receptors in the brain. Typical effects of psilocybin include significantly altered states of consciousness, experienced through visual and auditory effects, changes in perception, distortions of time; and a range of effects including a sense of awe, novel perspectives, existential and personal insight, dramatically heightened empathy and feelings of compassion, strong emotions, and unitive experience. With proper screening and preparation, psilocybin has a safe physiological and psychological profile. Psilocybin is currently the preferred compound for use in clinical research involving 5-hydroxytrptaminergic psychedelics because it has a shorter duration of action and suffers from less notoriety and stigma than other similar drugs.

Two recently completed clinical trials have assessed the effects of psilocybin on TRD in participants with BDII. The first study was a non-randomized controlled trial that demonstrated a single 25 mg dose of psilocybin with accompanying PAP led to a decrease in MADRS scores in all study participants (n=15) at the 3-week primary endpoint. The second study was a randomized controlled trial that included participants with both unipolar (n=27) and bipolar treatment-resistant depression (n=4), wherein all participants received at least one 25 mg dose of psilocybin with accompanying PAP (with the exception of one participant who dropped out of the study before receiving the study intervention). Participants had the opportunity to receive up to two additional 25 mg doses of psilocybin with accompanying PAP, if they were eligible to receive a repeat dose as per the study protocol. Both trials demonstrated that 25 mg of psilocybin resulted in a decrease of depressive symptoms in participants with treatment-resistant bipolar depression, without increased incidence of manic or hypomanic symptoms.

Beyond the clinical benefits observed, psilocybin has provided several new insights into the neurobiology of depression, with dozens of additional, ongoing mechanistic studies underway. Neuroimaging studies evaluating the effects of psilocybin in treatment-resistant (unipolar) depression (TRD) have provided surprising neurobiological insights that have called into question several assumptions of mood disorders. In an open-label TRD trial evaluating the antidepressant and neurobiological effects of psilocybin, increased activity of the right amygdala was observed in response to fearful and happy faces post-treatment. Psilocybin's antidepressant effects were associated with increased right amygdala responses to negative emotional stimuli, an opposite effect to previous findings with selective serotonin reuptake inhibitors (SSRIs). Wherein SSRIs mitigate negative emotions, psilocybin might allow patients to feel, confront and work through them. These findings also suggest that neurobiological targets and mechanisms required to alleviate TRD, may be different from non-resistant depression, where SSRIs are often effective by reducing amygdala response to negative stimuli. Notably, the impact of psilocybin on amygdala function varies inter-individually depending on baseline mood state. More specifically, in healthy volunteers, psilocybin has been shown to decrease amygdala response to emotional stimuli, whereas in TRD, psilocybin was associated with increased amygdala response. Evaluating the effects of psilocybin in TRBD may improve the investigator's understanding of the neurobiology of bipolar depression by dynamically evaluating altered amygdala function and associated changes in depressive symptoms over time.

Eligibility Criteria:
Inclusion Criteria:

1. Adults 18 to 65 years old.
2. Must be deemed to have capacity to provide informed consent;
3. Must sign and date the informed consent form;
4. Stated willingness to comply with all study procedures;
5. Ability to read and communicate in English, such that their literacy and comprehension is sufficient for understanding the consent form and study questionnaires, as evaluated by study staff obtaining consent;
6. Primary DSM-5 diagnosis of Bipolar II Disorder (BD-II) currently experiencing a Major Depressive Episode (MDE) without psychotic features as diagnosed by a mood disorder specialist and confirmed using the Mini-International Neuropsychiatric Interview (MINI);
7. Current MDE must be moderate to severe, as determined by the Hamilton Depression Rating Scale (HDRS-17) score greater than 20 with inadequate response to two or more adequate evidence-based treatment trials for bipolar depression, as per the 2018 CANMAT Bipolar Disorder Guidelines. Treatment trials are specific to current MDE rather than lifelong trials;
8. Ability to take oral medication;
9. Must be currently taking lamotrigine or planning on starting lamotrigine outside of the trial for the duration of the study, including the 1-month follow-up period, without changes in the medication;
10. Individuals who are capable of becoming pregnant: use of highly effective contraception for at least 3 months prior to screening and agreement to use such a method during study participation;
11. Individuals who are capable of fathering a child: use of condoms or other methods for the duration of study participation to ensure effective contraception with partner;
12. Individuals who are willing to taper off current medications for a minimum of 1-month prior to Baseline (V3, Day -1) and whose physician confirms that it is safe for them to do so;
13. Agreement to adhere to Lifestyle Considerations (section 4.5) throughout study duration.

Exclusion Criteria:

1. Pregnant as assessed by a urine pregnancy test at Screening (Visit 1) or individual's that intend to become pregnant during the study or are breastfeeding;
2. Treatment with another investigational drug or other intervention within 30 days of Screening (Visit 1);
3. Current symptoms of mania, hypomania or mixed features, as determined by the Young Mania Rating Scale (YMRS) score greater than 12;
4. History of mania or hypomania in the past 6 months as determined by psychiatric history;
5. Have a DSM-5 diagnosis of substance use disorder (excluding use of tobacco) within the preceding 12 months;
6. Have active suicidal ideation as determined by the C-SSRS and/or clinical interview Significant suicide risk is defined by suicidal ideation as endorsed by items 4 or 5 of the C-SSRS, OR active suicidality requiring involuntary inpatient treatment or recent suicide attempts within the past 3 months;
7. Any DSM-5 lifetime diagnosis of a schizophrenia-spectrum disorder; psychotic disorder (including but not limited to during previous mood episodes or substance-induced psychosis), bipolar I disorder, paranoid personality disorder, borderline personality disorder, or neurocognitive disorder as determined by medical history, the MINI clinical interview, and the International Personality Disorder Examination (IPDE) administered at V1;
8. Have contraindications to fMRI as determined by the MRI questionnaire;
9. Have a history of seizures;
10. Are taking anticonvulsants (with the exception of lamotrigine) or benzodiazepines (lorazepam up to 2mg/day is acceptable);
11. History of Steven-Johnson Syndrome (SJS) or suspected SJS as determined by medical history;
12. Any first-degree relative with a diagnosis of schizophrenia-spectrum disorder; psychotic disorder (unless substance-induced or due to a medical condition); or bipolar I disorder as determined by the family medical history form and discussions with the participant;
13. Presence of a relative or absolute contraindication to psilocybin, including a drug allergy, recent stroke history, uncontrolled hypertension, low or labile blood pressure, recent myocardial infarction, cardiac arrhythmic, severe coronary artery disease, or moderate to severe renal or hepatic impairment;
14. Presence of baseline prolonged QTc or Torsade de Pointes as measured by the ECG or a history of long QTc syndrome or related risk factors;
15. History of allergy to lamotrigine or psilocybin, or inability to tolerate lamotrigine during trial.
16. Participants who are unwilling or unable to take their lamotrigine (as prescribed by their most responsible physician) throughout the duration of the study, including up to the four-week post-dose visit, will be excluded from the study.
17. Use of classic psychedelic drugs (e.g., psilocybin, DMT, LSD, mescaline) within the previous 6 months of singing the informed consent form;
18. Use of intravenous or oral steroids within one week of the administration of psilocybin;
19. Use of S-Adenosyl methionine (SAM-e), 5-Hydroxytryptophan (5-HTP), L-tryptophan, and St. John's Wort one week prior to administration of psilocybin; and
20. Any other clinically significant physical illness including chronic infectious diseases or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if they take part in the study.