Pharmacotherapy and Ketamine Assisted Psychotherapy for Treatment-Resistant Depression: A Patient With Lifelong Self-Doubt and Self-Criticism

J Clin Psychiatry 2023;84(3):23ct14798
To cite: Yeung A, Sapirstein G, Crain L, et al. Pharmacotherapy and ketamine assisted psychotherapy for treatment-resistant depression: a patient with lifelong self-doubt and self-criticism. J Clin Psychiatry. 2023;84(3):23ct14798.
To share: https://doi.org/10.4088/JCP.23ct14798
© 2023 Physicians Postgraduate Press, Inc.
^aDepression Clinical & Research Program, Massachusetts General Hospital, Boston, Massachusetts
^bPrivate practice, Boston, Massachusetts
^cCenter for Group Psychotherapy, Massachusetts General Hospital, Boston, Massachusetts
^dDepartment of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
^eCenter for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, Boston, Massachusetts
*Corresponding author: Albert Yeung, MD, ScD, Massachusetts General Hospital, 6F, Bowdoin Sq, Boston, MA 02114 (ayeung@mgh.harvard.edu).

According to the Sequenced Treatment Alternatives to Relieve Depression trial, only 30% of participants achieved remission with selective serotonin reuptake inhibitor (SSRI) (citalopram) monotherapy (level 1); another 20% achieved remission after switching to a second antidepressant or psychotherapy or by combining a different class of antidepressant with citalopram (level 2), and the probability of remission decreased with each additional treatment trial.¹ While there is no consensus on a definition of treatment-resistant depression (TRD), many researchers have used “unsatisfactory response to two adequate trials of two different classes of antidepressants at optimum dosage for sufficient duration.”² A recent estimate of the 12-month prevalence of TRD, based on data from US insurance claims, concluded that 30.9% of people with medication-treated major depressive disorder (MDD) have TRD, which accounts for a large proportion of the national annual health care burden (56.6%), unemployment burden (47.7%), and productivity burden (32.2%) of medication-treated MDD.³ TRD was found to be associated with higher symptom severity, suicide risk, greater number of lifetime depressive episodes, and comorbid anxiety and anhedonia.^4,5 Comorbid physical illnesses, including autoimmune conditions, hypothyroidism, and cardiac or cerebrovascular diseases, and comorbid psychiatric disorders, such as substance abuse and personality disorders, can also negatively impact the outcomes of treatment of MDD.⁶ Certain personality and psychological characteristics may also contribute to TRD. Individuals with delays or deficits in the development of a self-concept, or view of the self, may become highly self-critical. They may develop intense feelings of inferiority, guilt, and worthlessness and feel that they have failed to live up to expectations and standards.⁷ Such individuals are highly prone to depression and increased levels of stress, which may reinforce a negative view of one’s sense of self. Experiencing a discrepancy between one’s actual self and one’s ideal or desired self is associated with depression.⁸ Also, individuals who are preoccupied with being flawless or perfectionistic and inclined to scrutinize themselves harshly are also prone to depression.⁹

Various pharmacologic strategies and neurotherapeutic devices are used for treating TRD.¹⁰ Pharmacologic approaches include optimization, drug substitution, combination, and augmentation. Optimization involves using medications that have worked for the patient in the past or increasing the dose of the existing antidepressant and lengthening the duration of therapy. Drug substitution involves changing from one antidepressant to another antidepressant, which could be in the same class or have a different mechanism of action. Combination involves the addition of a second antidepressant to the therapy regimen to obtain a complementary clinical effect. Augmentation involves adding a non-antidepressant agent, such as lithium, anticonvulsants, antipsychotics, thyroxine, bupropion, pindolol, or pramipexole, to the antidepressant. Neurotherapeutic treatments include transcranial magnetic stimulation, vagal nerve stimulation, and electroconvulsive therapy (ECT) for treatment of TRD. ECT is considered the gold standard treatment, with an estimated 65% efficacy.¹¹ If ECT fails, neurosurgery is available for severe TRD. However, its use is usually restricted to academic centers due to the invasiveness of the procedure. In addition to pharmacologic and neurotherapeutic devices, psychotherapies including cognitive therapy, interpersonal therapy, and psychodynamic psychotherapy are frequently provided as part of the treatment of TRD.

Ketamine, a dissociative anesthetic drug and an antagonist at glutamate N-methyl-d-aspartate (NMDA) receptors, is considered a novel antidepressant. Ketamine, 0.5 mg/kg, intravenous infusion over the course of 40 minutes, has been demonstrated to be an effective treatment for TRD in both research and clinical settings.^12,13 Observational studies have reported that ketamine administrated via intramuscular and oral routes is also effective for patients with depression and anxiety.^14–16 More recently, esketamine nasal spray, the S(+) enantiomer of ketamine, was approved by the FDA in 2019 for treatment of TRD in conjunction with an oral antidepressant.¹⁷ The bioavailability of intravenous, intramuscular, intranasal, oral, and rectal ketamine is 100%, 93%, 8%–45%, 17%–29%, and 11%–25%, respectively.¹⁸ While the available data provide only short-term outcomes, ketamine is now a novel treatment for TRD. It can be delivered by different routes, tailoring to the clinical setting, the desired speed of onset of action, and the patient’s preference.

In recent years, there has been a resurgence in the interest of psychedelic assisted psychotherapy (PAP) using psychedelics (hallucinogens) such as lysergic acid diethylamide (LSD), mescaline, 3,4-methylenedioxy​methamphetamine (MDMA), and psilocybin. These are serotonin 2A receptor (5-HT_2AR) agonists with promising results for treatment of end-of-life psychological distress, addiction, MDD, and posttraumatic stress disorder (PTSD).¹⁹ Psychedelics induce altered consciousness that is associated with feelings of bliss, ecstasy, unconditional love, interconnectedness, and oneness with all things, and the occurrence of such a consciousness state appears to predict positive mental health outcomes.²⁰ PAP can be conceptualized as experiential treatment in which specific pharmacologic actions temporarily induce modifications in brain functioning and conscious experience. When appropriately mediated, these can be deeply meaningful experiences that elicit emotional, cognitive, and behavioral changes. In general, PAP requires very few drug treatment sessions, accompanied by drug-free sessions before and/or after drug sessions, usually referred to as preparatory and integrative psychotherapy, respectively. With ketamine, positive results were obtained with 1 to 12 administrations; with MDMA, just 3; and with psilocybin and LSD only 2, while ibogaine may be effective after a single administration.²¹ During drug treatment sessions, patients are continuously monitored and supported by trained mental health professionals following available guidelines.²² During medication sessions, patients usually wear eyeshades, listen to instrumental evocative music, and are encouraged to stay introspective and open to feelings, be attentive to thoughts and memories, and feel free to engage in psychotherapy at any time.²¹ The (usually 2) cotherapists monitor the patient’s vital signs including blood pressure, pulse rate, respiration rate, and oxygen saturation; attend to the patient’s comfort and needs; address adverse events such as nausea, vomiting, and hypertension; and administer medication treatment when indicated. In addition, they provide therapy when the patient is ready to share and engage in conversation, offer emotional support if the patient manifests strong anxiety or fear, and manage overt agitation to prevent escalation or physical injury.

Ketamine, an NMDA receptor antagonist, is not considered a classic psychedelic. Yet, it has similar dissociative effects that have been observed to bring relief from negativity, increase openness, promote communication, provide access to difficult materials with less fear, offer relief from obsessive and depressive concerns, and integrate a sense of newness and healing.¹⁹ These properties make ketamine an excellent candidate for PAP, and, currently, ketamine is the only legal psychedelic medicine available to mental health providers for the treatment of TRD. Ketamine assisted psychotherapy (KAP) has been used for patients suffering from a variety of disorders, including MDD, PTSD, bipolar I and II disorder, obsessive-compulsive disorder (OCD), and substance use. While the literature on KAP is small, it shows promise as a novel intervention to be explored further in many treatment-resistant clinical conditions.²³ Similar to PAP, KAP clinicians meet with patients for 1–3 preparatory sessions to educate them about potential effects of ketamine, inform them about what happens during medication sessions and how best to engage in treatment, and guide them to select the psychological issues they want to focus on during medication treatment. In the first session, ketamine is usually given at a low sublingual dose to gauge the patient’s response, such as emotional changes, access to memories, or gaining new insights. In subsequent ketamine sessions, the doses will be titrated to optimize the patient’s therapeutic outcomes, which are frequently related to the levels of consciousness change. The therapists will then meet with the patient for “integration” sessions to process their experience in the ketamine sessions, as well as generate meanings and insights to be integrated into their cognitive framework.

Psychodynamic Perspective

Dr Laura D. Crain

Given his deep suffering, this patient sought out KAP hoping for rapid relief. Instead, he finds the pace of the ketamine-induced state to be fast and overstimulating such that he struggles to usefully integrate his experiences. He leaves the treatment saying that he finds himself “needing time for self-exploration and self-reflection.” In my experience, moments of insight are rarely dramatic, and are followed by long periods of integration and working through, on the road to psychic change.

Regardless of what treatment we employ, it is helpful to be grounded in a formulation. We learn that John is the “unplanned” baby of 6 from a large Catholic family. There is significant unresolved trauma in his life. He tells us that he was once held at gunpoint, but we don’t hear what he remembers about that experience or what it meant to him. He feels empty, no good, an underachiever. His father physically abused his older brothers and spared him; if he had more insight, the patient might be aware of survivor guilt in the wake of his brother’s suicide. Instead, John reports his idea that his brother’s suicide was caused by brother’s failure to self-actualize; despite his own achievements, he feels identified with this brother. His worst depression occurred after two major losses: when his wife left him for a woman, undoubtedly a devastating blow, and then a year or two later, after his brother’s suicide. There is a lot that this patient cannot yet access from his unconscious.

We could wonder if John has ever felt enough feelings during his life, or, upon reflection about his life, would be able to feel truly alive enough to sufficiently mourn his losses. This man has deep psychic wounds that could be revealed and worked through over time; a longer-term insight-oriented psychotherapy will be the opportunity for self-exploration and self-reflection that he needs. In the best case, ketamine helps to push the unknown to the surface, but, in the worst case, ketamine may represent this patient going into action mode—looking for a magic potion—to avoid a simpler talking cure that would enable him to bear painful feelings and insights.

Family Systems Perspective

Dr Margaret A. Cramer

The central feature of this individual’s experience is that, though he has tried virtually every treatment for depression, nothing has helped him. Despite a well-functioning life that includes a successful business, steady relationship, good health, regular exercise, and relatively mild depressive symptoms, he reports being distressed consistently for 40 years.

John’s early family relationships may contain clues to his long-standing suffering: Father was on a “pedestal,” yet was volatile and believed in corporal punishment; the first 10 years of his life were “bliss,” but then, inexplicably, filled with anxiety. Adulthood is burdened with convictions/worries that he isn’t “doing it right” or trying hard enough, or is underachieving.

The current treatment regimen can be understood as a re-enactment of the patient’s internalized family relational protocols. A successful life but an enduring experience as not living up to his potential creates a safe space where he achieves but never really enjoys, one that keeps him safe from, and from becoming, his volatile father. This compromise contains and expresses his rage at a critical but longed for parent. The patient imagines, for example, that his doctors are accusing him of not working hard enough in treatment, yet in a trick of mind that turns passive into active, the patient also becomes the harsh father who frustrates his treaters, enlisting them to try endlessly but to no avail. His doctors, too, aren’t good enough.

To help free John from the internalized family constellation alive in the treatment, his providers might attempt a paradoxical intervention. They might shift the focus of treatment from cure to learning coping skills to deal with his life as it is. By assuring the patient that he is not at risk of serious improvement while also assuring him of their continued availability, the internalized pressure that governs this patient’s life and the need for his compromised experience of it might begin to lift and, with it, open the possibility of the life satisfaction that has eluded him for so long.
 

Cognitive Behavioral Therapy Perspective

Dr Susan Sprich

Given the discrepancy between the patient’s relatively mild depression symptoms and his high subjective distress, I would suggest referring him for an evaluation to assess for attention-deficit/hyperactivity disorder (ADHD) and OCD, as either of these diagnoses might explain the gap between how hard he is working and his sense that he is not as successful as he should be. If the patient meets criteria for ADHD, this might be useful as a framework for him to understand this discrepancy. John might benefit from CBT aimed at providing more structure around his tasks, prioritization, coping with procrastination, and other skills designed to help with executive functioning. If he has OCD, it might cause him to work harder than other people to accomplish the same amount. In this case, he could benefit not only from psychopharmacologic intervention, but also from CBT (exposure plus response prevention).

Another way that CBT might be helpful with this patient is in helping him identify his core beliefs and chip away at core beliefs that are not serving him well. If John has a belief that “if I’m not perfect, I’m a failure” or something along those lines, he might be minimizing his success because he isn’t “perfect” by whatever definition he might be using. I would also recommend that the patient consider participating in one of the third-wave CBT therapies like dialectical behavior therapy (DBT)²⁴ or acceptance and commitment therapy (ACT).²⁵ Both focus on radically accepting both the past and present to help individuals move forward effectively. ACT has a strong emphasis on labeling thoughts as thoughts and not giving them too much power and on encouraging people to clarify their values and make sure that they are spending their time in a way that aligns with their values. Doing this would likely alleviate some of the patient’s distress. If he could learn and practice mindfulness, he could be more accepting and present. He could learn to label thoughts and emotions and simply let them be, rather than trying to control them, which often causes distress.
 

Ketamine Assisted Psychotherapy Perspective

Dr Fernando Espi Forcen

Data for ketamine and KAP are emergent and deserve further study. More research on the routes of administration is necessary as only IV ketamine and intranasal esketamine have received sufficient study in randomized controlled trials. Furthermore, more research on KAP (versus ketamine only) is particularly necessary as psychedelic assisted psychotherapy (eg, KAP) is a highly promising yet currently understudied area of inquiry.

In this case, the use of ketamine, and KAP more specifically, was a clinically reasonable treatment choice as John had tried a number of psychopharmacologic and psychosocial treatments and 2 modalities of neuromodulation. The clinicians showed reasonable judgment by starting with oral lozenges to assess tolerance and adding the booster later in the session to ensure an appropriate dose to treat the patient. Since John tolerated ketamine lozenges well, intramuscular (IM) ketamine was reasonable for the second KAP session. IM ketamine has greater bioavailability than ketamine lozenges; therefore, the dose used here was higher than the dose used in the first session. IM ketamine is more incisive and, as such, ideal for KAP. Patients receiving only ketamine for depression generally receive 6 to 12 treatments, whereas in KAP 1 or 2 sessions could potentially be sufficient to continue integration therapy without ketamine. Ketamine is generally well tolerated, and its side effects such as nausea, hypertension, and headache can be easily controlled in a clinical setting.

In contrast to traditional antidepressants that enhance serotonin, norepinephrine, and dopamine activity, ketamine’s proposed mechanism of action is antagonism of the NMDA receptors. The NMDA receptor is a receptor of glutamate, a major excitatory neurotransmitter. Dysfunction of the NMDA receptor affects cognition and behavior, as in various pathogenic and iatrogenic conditions, such as NMDAR encephalitis, amyotrophic lateral sclerosis, and dextromethorphan intoxication. NMDA receptor antagonism has been shown to improve depression.

In addition to its NMDA receptor antagonism, ketamine has other mechanisms of action that may contribute to its antidepressant effect. Ketamine antagonizes μ and has an agonist/antagonist action of κ-opioid receptor, antagonizes the nicotinic receptors, and agonizes the dopamine D₂ receptors. Another mechanism of ketamine that might explain its antidepressant effect is neuroplasticity. Ketamine appears to promote synaptogenesis in the medial prefrontal cortex and hippocampus, elevating the formation rate of dendritic spines in these areas that are traditionally affected by chronic stress and depression.²⁶ The auxiliary mechanisms should be further studied to determine their clinical significance.

Apart from the basic science aspects and neurobiological mechanisms, there may be a therapeutic role derived from the ketamine phenomenological experience. The psychedelic effects of ketamine, such as dissociation from mind and body, calmness, peacefulness, and euphoria—taken in the appropriate setting—may help the patient expand perception and insight.
 

Integrative Discussion

Dr Jonah N. Cohen

Treatment-resistant depression is associated with significant suffering and health care burden. Treatments of TRD included psychotherapy, neurotherapeutics, and pharmacotherapy, including ketamine. Clinical presentations of TRD are heterogeneous, with different symptom profiles, varying sociocultural and developmental backgrounds, and diverse characterological organizations. Drs Yeung and Sapirstein present the case of John, a man with lifelong depression who is treated with KAP and ongoing pharmacotherapy. John’s case is an excellent example of how using different therapeutic frameworks is essential in the conceptualization and treatment of TRD.

Drs Crain and Cramer examine some of the developmental, interpersonal, and intrapsychic underpinnings of John’s lifelong depression. Dr Crain explores John’s unresolved traumas (eg, brother’s suicide, his wife’s departure) and the importance of mourning and metabolizing his losses. Dr Cramer discusses how John leads a successful life but feels as though he has failed to live up to his potential, a compromise John has made to keep himself feeling psychological safe but also in pain. Like Drs Crain and Cramer, I believe an appreciation for the developmental and characterological elements of John’s TRD is essential in formulating the drivers of his suffering. John must learn to relate to others and to himself in new and healthier ways. To do this, John must mourn profound interpersonal disappointments and mourn the loss of an idealized view he has had for himself. John must also navigate the tension between experiencing his clinicians as capable of disappointing him but also as capable of reliably caring for him. Of course, this is a long and challenging therapeutic journey, and when someone has suffered as long and as intensely as John has, one should think pragmatically and creatively.

Dr Sprich discusses essential diagnostic considerations that may help to explain aspects of John’s TRD. John’s procrastination and other challenges around executive functioning may be related to ADHD or an obsessional process, which opens up other treatment possibilities such as cognitive behavioral therapy for ADHD or OCD, highly effective and often shorter-term interventions. Moreover, Dr Sprich recommends ACT and/or DBT and discusses the role of acceptance in these therapies, which converge with Drs Cramer and Crain’s focus on mourning painful realities where there is a delta between the actual and the ideal.

Finally, Dr Forcen discusses the power of ketamine and KAP. Ketamine has a different mechanism of action than traditional antidepressants, making it a good option when more traditional options have led to a suboptimal therapeutic response. Dr Forcen also discusses how ketamine may enhance neuroplasticity and insight. Crucially, KAP might help facilitate insights and affective shifts in John’s relationship to others and himself in a shorter period than more traditional longitudinal psychotherapies. On the other hand, John experienced some challenges surrendering to KAP, and one must be cautious in making overpromises. Overall, effective treatment, particularly for clinical presentations such as TRD, requires putting aside theoretical allegiances in exchange for a flexible and creative therapeutic approach.

Submitted: January 25, 2023; accepted February 24, 2023.
Published online: April 5, 2023.
Relevant financial relationships: Dr Sprich receives royalties from Springer and Oxford University Press and honoraria from the Association for Behavioral and Cognitive Therapies. The other authors report no relevant financial relationships.
Funding/support: Cross Talk is financially supported by the Endowment for the Advancement of Psychotherapy at Massachusetts General Hospital.
Role of the sponsor: The funding agency had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication.
Statement of de-identification: Information has been deidentified to protect patient anonymity.