While ketamine has been proven to decrease depressive symptoms in patients, the drug, like many others, has many harmful side effects. The most notable are potential addiction and withdrawal from overuse and dependence. Other notable side effects include but are not limited to: disassociation, hallucinations, hypertension, nausea, and headaches. Therefore, patients should consult a healthcare professional before starting any treatment plans.

Adverse Effects of Ketamine

Ketamine, a rapid-acting anesthetic and NMDA receptor antagonist, has been investigated for use in treatment-resistant  depression. When infused in sub-anesthetic doses over a short period (e.g. 40 minutes), ketamine has been shown to have rapid antidepressant effects that can last for up to 4 weeks in some patients.

Scripps College

Treatment resistant depression is generally acknowledged as depression which has not responded to a minimum of two different antidepressant medications. It is fairly common, with 60-75% of depressed patients meeting this criteria with a high severity and duration and increased exhibition of physical and mental symptoms that lead to higher dysfunction.

Treatment Resistant Depression

- Monoamine hypothesis
- Monoamine Oxidase (MAO)
- Reserpine
- Tricyclics
- Selective serotonin reuptake inhibitors (SSRIs)

Drug Treatments for Depressive Disorders

Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., Charney, D. S., & Mathew, S. J.. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. American Journal of Psychiatry, 170(10), 1134–1142. https://doi.org/10.1176/appi.ajp.2013.13030392

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial

Corriger, A., & Pickering, G.. (2019). Ketamine and depression: a narrative review. Drug Design, Development and Therapy, Volume 13, 3051–3067. https://doi.org/10.2147/dddt.s221437

Ketamine and depression: a narrative review

Mindfulness-Based Cognitive Therapy (MBCT) can help patients with treatment resistant depression minimize depression relapse and current symptoms by reducing depressive rumination and increasing self-compassion and mindfulness.

Mindfulness-Based Cognitive Therapy and Treatment-Resistant Depression

Using ketamine for treatment-resistant depression

A research study found that out of 129 patients with treatment resistant depression, 82.9% had another mental disorder, 82.2% were diagnosed with a personality disorder, and 69.8% had severe physical health ailments. In addition, 44.9% attempted suicide at least once in their lives, 79.8% experienced significant childhood trauma, and a vast majority reported a poor quality of life. These results show that TRD is a complex form of depression that requires further research. 

Demographic of Individuals with TRD

Researches studied 33 out of 80 TRD patients who agreed to adopt a pet as a means of animal therapy. The treatment method proved to be successful, as the patients who chose to adopt a pet reported an improvement in depressive symptoms and had better remission and response rates than individuals in the control group.

Pet Adoption as a Treatment Method

- A risk of taking SSRIs
- Many over-the-counter drugs may synergize with the drugs to push synaptic serotonin levels too high
- Symptoms include confusion, muscle spasms, and fever

Serotonin Syndrome

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs used to treat conditions like depression, which is often associated with low serotonin levels. Unlike agonists or antagonists that bind to receptors, SSRIs work by blocking the reuptake process. This action prevents unused serotonin from being reabsorbed by the presynaptic neuron, allowing it to remain in the synaptic cleft for a longer period. The extended presence of serotonin enhances its interaction with postsynaptic receptors, thereby strengthening its overall effect. Common examples of SSRIs include Prozac, Paxil, and Zoloft.

SSRIs and SNRIs

Tricyclic (or heterocyclic) antidepressants inhibit the reuptake of serotonin and/or norepinephrine, and are thus called due to their three (or more)-ring chemical structure. Some examples include:

- Amitriptyline (Elavil) 
- Nortriptyline (Aventyl)
- Maprotiline hydrochloride (Ludiomil)
- Desipramine hydrochloride (Norpramin)
- Clomipramine (Anafranil)

A similar drug is Bupropion (Wellbutrin), which is an aminoketone that weakly blocks norepinephrine, serotonin, and dopamine reuptake.

Tricyclic Antidepressants

MAOIs inhibit the breakdown of the enzyme that breaks down monoamine neurotransmitters. Some MAOIs have antidepressant effects, including:

- Phenelzine (Nardil)
- Isocarboxazid (Marplan)
- Tranylcypromine (Parnate)

Monoamine Oxidase Inhibitors (MAOIs)

Psychedelics, in particular LSD and psilocybin, have been investigated as potential treatments for depressive symptoms. There is evidence for short-, medium-, and long-term usefulness in both micro-dosing and regular studies. In addition to the potential cognitive stimulation (LSD) or emotional well-being effects (psilocybin), these treatments are generally well-tolerated in clinical and general populations. In addition, MDMA has received breakthrough treatment status with the FDA for the treatment of PTSD.

Potential clinical uses for psychedelics

Caffeine has been shown to increase the antidepressant effects of repeated transcranial magnetic stimulation in humans and the antidepressant-like effects of SSRIs, SNRIs, and atypical antipsychotics in mouse models. The proposed mechanism for this is that caffeine's adenosine receptor antagonism increases downstream production of serotonin, dopamine, and norepinephrine.

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