Depression, post-traumatic stress disorder, suicidal ideation and ketamine: a case report

Abstract

Background

Ketamine treatment presents a novel approach for addressing refractory conditions, such as major depressive disorder, suicidal ideation, and posttraumatic stress disorder, which often co-occur and pose significant challenges for clinicians. This study explores the clinical and electrophysiological outcomes of ketamine treatment in two cases, shedding light on its potential efficacy and mechanisms of action.

Case presentation

The first case involves a 56-year-old Caucasian male with chronic posttraumatic stress disorder and suicidal ideation, and the second case involves a 52-year-old Caucasian female with treatment-resistant major depressive disorder. Both patients opted for ketamine treatment after years of unsuccessful interventions. The male patient received nine ketamine infusions over 18 months, while the female patient received five infusions over one month. Symptom improvement was accompanied by distinct electrophysiological changes, as observed through electroencephalogram and evoked electroencephalogram responses. These changes persisted for several months post-treatment, offering hope for individuals grappling with challenging chronic conditions.

Conclusion

Ketamine infusions resulted in significant and sustained symptomatic improvement in both cases, accompanied by distinct electrophysiological changes indicative of altered brain function. These findings highlight the potential of ketamine as an alternative treatment for refractory conditions, such as major depressive disorder and posttraumatic stress disorder, offering relief and functional recovery for certain patients. Further research is warranted to elucidate the underlying mechanisms and optimize treatment protocols.

Introduction

Major depressive disorder (MDD), suicidal ideation (SI), posttraumatic stress disorder (PTSD), and substance abuse can occur concurrently, and present well-known challenges for clinicians [1,2,3]. Ketamine has been used as an anesthetic and its “dissociative experiences” may also provide benefits for reducing symptoms of these disorders [4,5,6,7,8,9]. It induces clear physiologic changes, as reported in functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) studies [10,11,12,13,14], and increases brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) concentrations in the brain, thus reversing the effects of stress on generally excitatory glutamate synapses [15]. Additionally, ketamine also upregulates GABA-modulated inhibitory neurotransmission [16], thus improving synaptic connectivity, and possibly triggering functional recovery of neural networks damaged by the chronic stress associated with conditions, such as MDD, PTSD, and substance abuse [17,18,19,20]. These effects can be more sustained because of its trophic effects on neurogenesis [21]. From a practical perspective, these new synaptic connections manifest as a change in mindset and ability to reframe thinking, which then also extends to instituting pragmatic changes in one’s life to realize that shift in psychological paradigm [22].

The case studies reported here involve two patients who selected ketamine treatments for their heretofore refractory conditions. These patients were tracked over the course of their treatments by EEG with evoked response potential (ERP), symptom reports, suicide ideation scales, and subjective narratives of the patient experience. The first patient, suffering from PTSD with SI, was followed over the course of 18 months and nine ketamine infusions. The second patient, suffering MDD, was followed for 1 month over five treatments. The magnitude and duration of symptomatic and electrophysical changes in these patients both pre- and post-treatment were explored. The case studies reported here offer a unique perspective on the use of ketamine treatment for refractory conditions, such as MDD, PTSD, and SI, shedding light on its potential efficacy and mechanisms of action in real-world clinical settings.

Methods

EEG/ERP measures

We focus on three relevant EEG/ERP measures that are readily accessible and useful for tracking: EEG alpha peak distribution, peak frequency (PAF), and the P300 ERP amplitude (P300V). The alpha frequency, between 8 and 12 Hz, is the dominant frequency of the EEG and can provide information related to central nervous system (CNS) and cognitive functioning. An individual’s PAF is considered a stable marker of a neurophysiological trait and can therefore provide longitudinal information [23, 24]. Slowing of the EEG has been found to indicate CNS pathology. In particular, PAF slowing is common for patients with dementia. Some studies have also shown slowing in patients with PTSD and MDD [25].

The distribution of alpha amplitudes across the scalp is another important measure since it has been reported that patients with PTSD and/or MDD show a left–right asymmetry in amplitude distribution, whereas patients with prolonged concussion symptoms can express more frontal dominant alpha activity (as opposed to normally occipital dominant alpha) [26].

ERPs are a measurement of the EEG signal time-locked to the onset of a given stimulus. The auditory oddball P300 protocol, one of the most widely studied, assesses the brain’s cognitive ability to recognize an odd tone as different from a common tone. A decrease in P300V is observed in various conditions accompanied by a decline in cognitive function, including dementia, trauma, substance abuse, depressive disorders, PTSD, and cardiovascular health [27,28,29].

Procedure

After clinical interviews and assessments, including the Suicidal Ideation Attributes Scale (SIDAS) [30], the patients received a baseline EEG scan with a 4-minute oddball audio ERP using the WAVi^® system, following the same procedure described elsewhere [26, 29, 30]. The EEG study was approved by the solutions institutional review board and written informed consent was obtained from the participants before scanning.

Results

Case 1

The first patient was a 56-year-old Caucasian male who reported being a non-smoker and abusing alcohol from the age of 15 to 45 years (sober last 11 years). He struggled for years with symptoms related to PTSD and MDD with at least one suicide attempt (which he attributed to his pharmaceutical prescriptions). There was no family history of PTSD or MDD noted. After many failed treatments, he decided to try ketamine as a treatment option. He received his first of nine infusions (all from two licensed facilities) in April 2021. Before his first treatment he had a SIDAS score of 40/50 (> 21 considered high risk), reporting suicide ideation “for as long as I can remember” and hypervigilance where “I was not able to go to bed without multiple automatic weapons at my bedside.”

The results of EEG/ERP testing and symptom outcome are presented in Fig. 1 and Table 1. At the original baseline session, the patient was not on any medication or supplements. While he exhibited signs of PTSD and SI, none of the typical EEG/ERP patterns for PTSD were observed [25]. In particular, the EEG spectra were normal (in all frequency bands) with no apparent asymmetries noted, and his P300 amplitude (9 uV) was in the normal age-matched range (7–17 uV) [24, 30].

Fig. 1

Peak frequency and P300 response trajectories before (session one) and after ketamine treatments for patient 1 (dashed lines represent expected test–retest variances [24, 30])

Table 1 Symptom and brain trajectories following ketamine treatments

The second scan, performed 16 days after the first ketamine infusion, showed a dramatic reduction in both the P300 amplitude and PAF, with alpha amplitude shifting to the front, accompanied by dramatic symptom improvements. Figure 1 shows both P300 amplitude and PAF declining well beyond personal variance expectation, where PAF is otherwise considered to be a stable marker of a person. This unusual pattern of sudden P300 cognitive-resource reduction (or reallocation) and alpha shifting to the front is similar to what has been reported in concussion and prolonged concussion [26, 29]. While these changes may be expected during ketamine treatment, they were not expected to persist 16 days after treatment. The accompanied duration of symptom resolution is also noteworthy.

In the third scan (second post-treatment scan) we see the same electrophysical trajectories as the second scan (first post-treatment scan), except even more pronounced alpha shifts to the front. The duration of these changes, and corresponding symptom improvement, linger up to 58 days after treatment as evidenced by the fourth scan. The following scans (after third and fourth treatments) represent a slow return to normal of the alpha distribution while symptoms continued to improve, but the PAF falls to its lowest point and the P300 is unstable. The final scan, taken 78 days after the ninth and final treatment, indicated normalization of PAF and alpha distribution, while the P300 response failed to return. (In Fig. 1, note the stability of the alpha topo in Table 1 between scans 1, 6, and 7).

Symptom resolution persisted up to day 78 post-final treatment, with the associated SIDAS at 2/50 (in contrast to the 40/50 at the time of the first scan). During the entire course of treatment, symptoms remained improved compared with the initial baseline. According to the patient: “the general trend line from the very first treatment has been up.”

Case 2

The second patient was a 52-year-old Caucasian female who reported being a non-smoker and abusing alcohol from the age of 14 to 23 years (sober last 27 years). Her medical history includes migraine headaches, MDD, and bipolar disorder. There was no family history of MDD or bipolar disorder noted. As with patient 1, after years of unsuccessful interventions, she tried ketamine infusions as a treatment option, with EEG/ERP scans pre- and post-treatment. She received her first treatment on 5 April 2022 and her fifth and final on 18 April 2022 from a licensed facility under the guidance of a certified nurse practitioner.

The results of the EEG/ERP testing and symptom outcome are presented in Fig. 2 and Table 2. At the original baseline session, she was not taking medication or supplements and complained of anxiety and depression but scored low on the SIDAS scale. No major EEG/ERP abnormalities were noted, except that her PAF, 11.5 Hz occipitally, was slightly above the age-matched reference range (9–11 Hz) [24]. Her EEG spectra were normal with no apparent asymmetries, and the P300 amplitude (10.6 uV) was in the normal age-matched range (7–18 uV) [30].

Fig. 2

Peak frequency and P300 response trajectories before (session one) and after ketamine treatments for patient 2 (dashed lines represent expected test–retest variances [24, 30])

Table 2 Symptom and brain trajectories following ketamine treatments

After her first treatment, and between treatments, she reported being more “hopeful, peaceful, relaxed, and at ease.” While still experiencing some anxiety and fear, she reports feeling “overall hopeful and confident everything will work out okay and [that] I will be able to handle whatever happens.”

At the time of the second scan, performed 5 days after her final ketamine infusion, she reported: “these treatments have totally transformed me and my life. I am amazed at how different I feel and how much better I am getting along with others.” These symptomatic improvements were accompanied by a dramatic increase in P300 amplitude but with no change in alpha amplitude or PAF beyond expectation (Fig. 2). It is important to note that her increased brain response to the treatment was the opposite of patient 1 whose P300 response decreased and remained as such.

Discussion

Ketamine infusions had a reported effect on improving the PTSD, MDD, and/or SI symptoms for these patients, accompanied by clear electrophysical brain changes as measured by common EEG/ERP markers associated with cognitive function and various conditions. The most profound electrophysiological change for patient 1 contending with PTSD/SI involved a significant reduction of the brain’s P300 response after the first treatment accompanied by low suicidal ideation. This could be interpreted as a “brain reset” or shift in psychological paradigm, as commonly described [22]. These symptomatic and P300 changes lasted 78 days beyond treatment, supporting the idea that enduring effects occur. These have been hypothesized to be related to the interaction of ketamine with several other receptors central to synaptic connectivity in certain pathologies [16]. This unusual P300 decrease followed by an increase of the PAF is also interesting and worthy of further study. Patient 2 responded differently. While her MDD symptoms resolved, her P300 response increased well above expectation. Again, if new synaptic connections manifest as a change in mindset and ability to reframe thinking [16], then this may correspond to different electrophysical responses as seen here.

Of course, questions remain: were these symptomatic improvements a function of cognitive resource reallocation? How does the decrease in PAF in patient 1 correlate with the low P300, and does it reflect neural inhibition post ketamine? Will symptoms return with full brain normalization (return to baseline P300)? Despite clear electrophysical changes, was there a placebo effect?

While these patients experienced different electrophysical trajectories, and while their symptomatic trajectories may not be representative of all patients who receive ketamine infusions, the treatment did have a positive effect on these patients suffering refractory conditions. These effects persisted for months and coincided with clear changes in electrophysiology and brain function, albeit unique for the two different patients.

Limitations

This is a presentation of two patients who received ketamine and saw positive results. It is not a statistically significant sample nor is it a double-blinded study intended to predict patient outcomes at large. Such is the nature of case studies, which in this instance is to present a unique therapeutic approach.

Conclusion

Ketamine infusions for these two patients suffering different refractory conditions seemed to correspond with symptomatic improvement that lasted many months, coinciding with clear changes in electrophysiology and brain function. The physiological changes accompanying symptom improvement support the efficacy of treatment in these cases, providing a potential alternative for certain patients suffering chronic conditions that are difficult to treat, such as major depression or posttraumatic stress disorder.