Clinical Overview of Depression
The following is an incredibly detailed clinical overview of depression. I’ll be explaining the established treatments and how exactly they work with some people and not others. I will also touch on the remedies which aren’t common knowledge, and then detail new and emerging treatments—which so far are looking really promising. An essential part of treatment, in my view, is also understanding. So, when explaining the various treatments, I'll also describe what it is that makes them effective, and so essentially by the end of this, you’ll have a complete picture of what is understood as it relates to the causes and physiological abnormalities seen in depression, as well as the clinical treatments for it.
Depression is often used synonymously to encompass a range of depressive disorders. These are: Disruptive mood dysregulation disorder, major depressive disorder (including the major depressive episodes), persistent depressive disorder, premenstrual dysphoric disorder, substance-induced depressive disorder, and other specified/unspecified depressive disorders. This article will be covering depression related to these disorders, it will not be covering depression associated with bipolar affective disorder, or severe depression with psychotic features/suicidal ideation/psychomotor retardation/or catatonia. This will often require additional management, potentially initiated in hospital settings, which may include: ECT, augmentation with antipsychotics, mood stabilisers, or other controlled medications, amongst the use of other medical devices (e.g TMS).
Vague Goals Produce Vague Results
Depression in and of itself is a mental state which is very broad. To adequately address and treat depression, it is absolutely essential to identify the cause, precipitating factors, and the exact nature of the state (done properly this will include a thorough history and also the screening for particular specifiers that often accompany the state, which allows for a more specific diagnosis of the particular subtype of depression). For instance, is this depression accompanied by anxiety, insomnia, guilt, panic, anhedonia? Vague goals produce vague results—and so it's essential to identify both the cause and nature of a depressive episode—as this often dictates not only the psychotherapeutic approach but also the medication that may be most appropriate.
A Word Of Caution
When patients present having recently experienced, or still experiencing, certain unfortunate circumstances e.g., loss, unemployment, etc.—I emphasise to them that this, in and of itself, is not a psychological problem—it's an actual problem. The depression that results is often a reaction to one or more situations that is either maladaptive or excessive in nature. Then after some time this can result in what would be defined clinically as a major depressive episode. But the situation or situations which prompted the reaction often persist. In actual fact, what I normally see when assessing someone experiencing a state of prolonged depression is what was initially, or still is, something that more closely resembles what is referred to as ‘adjustment disorder with depressed mood’. The difference between a major depressive episode which occurs as a response to acute stress, and adjustment disorder with depressed mood, is the severity of the episode, and not necessarily the causes or even the long-term prevention. The reason I state this is because we all vary in the way we cope, and respond to stressful situations. Some of us are blessed with this amazing ability to manage acute stress, or even just live a comparatively fortunate life where we are exposed to less of it. However, there is no escaping the fact that there are still fundamental lifestyle or even behavioural factors we all need to attend to, in order to maintain a remote level of psychological stability. And often, especially for more severe and long-standing depressive episodes, these fundamentals are simply not present—and so it pays to be especially cautious not to over-medicalise things, in the sense that it’s our sole priority. I have discussed these fundamentals in another article, however this article aims to focus solely on the pathophysiology and medications available. I'll start off now with explaining the gold standard medications used currently to treat depression, and what it is exactly that they do.
Established Medications
The medications currently prescribed are largely based on the monoamine theory which proposes that insufficient activity of monoamine neurotransmitters is the primary cause of depression. The monoamine transmitters are: serotonin, norepinephrine, and dopamine.
This theory has been called into debate recently, and for good reason—as the rationale behind solely pursuing this as the pathology of depression is questionable. Thankfully, the emerging treatments are beginning to involve other systems that are showing to play significant roles in the pathophysiology of depression. However, with that being said, there is no doubt that the antidepressant medications that increase the availability of these particular neurotransmitters are beneficial for most—with a meta-analysis performed recently looking at the effects 21 different antidepressants had on MDD. There is a clear advantage shown to taking these when compared to a placebo. So, although there is obviously much more to the cause of depression than simply these particular neurotransmitters, there is no doubt that abnormalities in the transmission of these networks play a large role.
So, as previously mentioned, the monoamine transmitters are: serotonin, norepinephrine, and dopamine. A rule of thumb, as it relates to our subjective experience, and note that this is purposely oversimplified: Serotonin generally relates to mood (depletion equates to low mood, guilt, grief), norepinephrine generally relates to energy levels (depletion can often equate to exhaustion), dopamine generally relates to motivation/ability to experience pleasure (depletion equates to anhedonia).
All of these current antidepressants interfere with one or more of these neurotransmitters. These antidepressants are:
SSRIs (selective serotonin-reuptake inhibitors)—the most commonly prescribed medication class.
SNRIs (serotonin-noradrenaline reuptake inhibitors)—Examples of this being venlafaxine, or duloxetine.
Atypical antidepressants. The main ones are bupropion (which is a norepinephrine-dopamine reuptake inhibitor) and mirtazapine (which essentially leads to an increase in the release of norepinephrine and serotonin).
No consistent differences in safety or efficacy have been shown between either the classes or the individual antidepressants. Choice of drug should therefore be informed based on other factors—such as side effect profiles and nature of depressive episodes. For example, if concentration and energy levels are concerning, an NDRI or SNRI might be the first choice, if insomnia is present—then potentially mirtazapine may be the best first choice, or if weight gain is a concerning factor—then potentially some of the more stimulating SSRIs such as fluoxetine may be helpful. Future research is now directed towards pharmacogenetics, which is interested in identifying the genetic differences which give rise to the varying improvement and also side effect profiles that different individuals experience with the same antidepressant. At the moment it’s largely a guessing game as it relates to deciding on the optimal antidepressant for each individual, and so if any of you are struggling with trialling antidepressants (as in starting and stopping different types because of side effects or just that they weren’t effective)—don’t worry, you are not alone. It often takes a number of attempts trialling different antidepressants to find one that may work for you.
Emerging Medicines
Moving onto the emerging treatments. There is a consensus that there is a growing need for more effective antidepressants. The new treatments being trialled that look promising relate to the following:
Interfering with the pathologies in the monoaminergic systems mentioned previously. These monoamines are serotonin, dopamine, and norepinephrine.
Interfering with the emerging understanding of the role inflammation plays in depression.
Interfering with the emerging understanding of the role hormones play in depression, specifically thyroid, sex hormones, and the HPA axis involved in the stress response.
Inducing plasticity of neuronal networks—based on observations of depression as being a state of a reduced ability to make the appropriate adaptations to stress or negative thought patterns.
Interfering with the emerging understanding of the role the glutamatergic system plays in depression. This system regulates another neurotransmitter named glutamate, which is the most abundant excitatory neurotransmitter in the brain.
Dextromethorphan/bupropion— A combination of Dextromethorphan (a glutamate modulator) and bupropion (which is a norepinephrine-dopamine reuptake inhibitor currently used in depression). This has shown to be very effective in trials—and is now licensed for MDD in the US. Trials demonstrate that it is more effective than bupropion alone. An additional point is that the therapeutic effects of this medication have been observed within 1-2 weeks of starting treatment and are sustained following this. Most current antidepressants often take a minimum of 4-6 weeks to take effect, so this is a really promising finding.
Thyroid Hormone—A small amount of evidence suggests that the administration of either T3 or T4, which are the thyroid hormones, can be effective when given to those with treatment-resistant depression, despite those individuals having normal thyroid levels.
Botox—Short for botulinum toxins, is most widely used for cosmetic purposes. Interestingly, there has been a recent exploration into its potential effects for those with depression. The studies performed have been quite successful in that they consistently show a reduction in symptom severity in those with depression that received botox. There is likely a number of explanations at play, and I don’t doubt that self-esteem may be an aid—the major theory into how it may be effective, however, is in relation to the reduction of negative feedback from the face that occurs after a botox course. This is essentially because it reduces the ability to frown.
Ketamine—Ketamine is a dissociative anaesthetic. Its use in depression is at lower doses and delivered either intravenously or nasally. It works as an NMDA receptor antagonist. Most evidence demonstrates that its effect at alleviating symptoms of depression is rapid (within roughly 40 minutes) and significant, but the effects are short-lived, with the positive effects usually diminishing at roughly two weeks after a single dose. The interest in ketamine in this field is more so in relation to what it is exactly that makes it so effective, being that it works in completely different ways to the existing medications, alongside its utility in assisting psychotherapeutic practices (psychedelic-assisted psychotherapy). It’s thought that the antidepressant effects ketamine induces, are not solely due to its dissociative properties, but when used in combination with therapy, the longer term effects are thought to be due to its effects on promoting neuroplasticity. This brings me on to the next emerging treatment, which likely works via this mechanism— in its ability to promote both structural and functional changes in our brain circuitry. This emerging treatment is the psychedelic compound psilocybin.
Psilocybin
When ingested, the body quickly converts this to psilocin, which is an agonist at multiple serotonergic receptors—with the highest affinity to the serotonin 2A type. First, I'll go into the results from the studies to date, and then explain how exactly we think it’s so effective.
At least six clinical trials have reported improvements in depressive symptoms over the last 15 years. Most studies include one or two administrations of psilocybin, and supported psychotherapy. These studies are pretty consistent in that there is a significant improvement in depressive symptoms reported and observed by the subjects. What’s even more promising is that these effects are long-lasting with follow-up studies now demonstrating that the significant reduction of symptoms recorded persists after 12 months. In terms of success rate, I'll refer to the most relevant study— in that it was recent, done specifically on individuals with major depressive disorder, and that it was a high-quality RCT. This study demonstrated that 71% of the participants on both week 1 and week 4 after treatment experienced a reduction in depressive symptoms by over 50 percent. And of these participants, 54 percent experienced complete remission—meaning they no longer fit the criteria for clinical depression. This is clearly very impressive.
Psilocybin is most commonly known due to it being the active compound in magic mushrooms—and the effects following ingestion of psilocybin are commonly referred to as a ‘trip’. The acute subjective changes, so i.e., the perceived experience, during trips are usually that of a significant change in thought pattern, behaviour, and this unique experience of ego dissolution. And when I say ego dissolution, I’m referring to this experience of the perceived boundary that we all have between the self, and the world we inhabit—momentarily breaking, or at least becoming less apparent. This in itself can be an extremely profound experience. Most of us live our lives holding on to this self-constructed identity of ourselves. Some of this sense of self is necessary to play our role in daily life, however a lot of it isn’t. And it is exactly this sense of self, which is used synonymously with ego here, that is responsible for this boundary that we perceive to be present between us and the outside world. This disconnect between our ego, and everything outside of it, often causes, or at the very least heightens the mental suffering we often endure. And so this ego dissolution, the feeling of letting go, however temporary, can be extremely profound.
That’s the subjective experience often reported—but what’s of my main concern here, however, is just how exactly this compound manages to induce these long-lasting effects. Effects that persist far beyond the metabolisation and excretion of this compound. The only feasible answer to this relates to neuroplasticity. I.e., both the structural and functional change of neuronal networks that were responsible for the previously depressive states.
How Neuroplasticity occurs in Psilocybin
Neuroplasticity as we know, simply put, is the ability of the neuronal networks within our brains to change through growth and reorganisation. It can do this functionally (in the ways that neurones behave) and structurally (in the way neurones are structured).
Our neocortex is composed of six layers. Psilocybin stimulates 5-HT2A receptors found in layers 5 and 6 pyramidal neurones, as well as on GABAergic interneurons. The net effect appears to be the excitation of layer 5 pyramidal neurones and increased levels of the neurotransmitter glutamate, resulting in greater stimulation of a particular type of glutamate receptor named AMPA receptors. The molecular pathways (such as the mTOR pathways, and others) which follow after the stimulation of this receptor are outside the scope of this section as it gets very technical (I’ll link the studies below for those who are interested in the details). However, the takeaway is that this AMPA receptor stimulation triggers a positive feedback loop leading to sustained AMPA activation. And it is the sustained activation of both AMPA receptors and mTOR, as well as activity in 5-HT2A and other glutamate receptors, which is necessary for the enhanced neuroplasticity that continues to occur following stimulation with psilocybin. These neuroplastic effects remain local to the neurones stimulated that express these 5-HT2A receptors, because the molecular pathways triggered act locally in the place in which the receptors had been activated. And so, in other words, the structural and functional effects that psilocybin may have on brain circuitry, are likely to be in areas that are dense with these 5-HT2A receptors.
Type and Timing of Neuroplasticity That Occurs After Ingestion of Psilocybin
Psilocybin enhances neuroplasticity in the following ways: enhanced dendritic growth, including the growth of dendritic spines, enhanced synaptic growth, and the up-regulation of plasticity-related genes. The data suggest that various signs of enhanced neuroplasticity arise within 1–6 hours, taper off within five days, though last for at least one month after treatment with psilocybin— meaning these neuroplastic changes are long-lasting. For future research— longer follow-ups are necessary to get a clearer picture of exactly how long-lasting these changes remain in effect.
The Pathophysiology of Depression and Where Psilocybin Induced Neuroplasticity Occurs
I am first going to highlight the abnormalities that have been observed in the structure and function of those with depression. Depression is complicated and multifaceted. But at least as it relates to arguably the most significant component to the cognitive aspect which characterises depression—being a kind of negative state of perpetual rumination—well, we can do a good job at explaining what could be going on here, with the neuroimaging studies performed so far. Specifically, I’m going to speak of what is commonly referred to as the triple network model comprising of three networks: The Default Mode network, the Salience network, and the Executive network. Each of these networks consists of a group of interconnected brain structures, which together form a functional system.
First, the DMN. Its name comes from the fact that it's most active whenever we are not engaged in an activity which demands our attention. Often, when we are in a state of wakeful rest, we engage in thought that often doesn’t have an explicit goal in mind. This state often leads to daydreaming, recalling memories, envisioning the future, thinking of others, abstract conceptualisation, to name just a few. This, as a collective, is often referred to simply as mind wandering.
The EN is the network responsible for executive functioning often needed for goal-oriented, cognitively demanding tasks. The SN can be seen as the bridge between both the DMN and EN. It is responsible for modulating the switch between the internally directed cognition of the default mode network and the externally directed cognition of the executive network.
As it relates to these three networks, depression is characterised by a hyperconnectivity and subsequent overactivity of the DMN. To add to this, we see a hypoconnectivity between the DMN and other higher-order brain networks—including the EN and SN. So, we get this excessive mind wandering caused by this overactivity of the DMN, but you also have a reduced ability to divert attention away from this perpetual and often negative mind wandering as a consequence of these weak connections to the higher-order networks that are responsible for doing this.
Where Psilocybin comes in is in its observed role in altering the connectivity of these networks. Interestingly, the serotonin 2A receptor is highly expressed in a pattern that resembles a map of the DMN, SN, EN and the connections between all of them. If you remember, I previously spoke about the fact that the neuroplastic changes occur local to where the serotonin 2A receptors that psilocybin works on are expressed—and as expected, this is what has been shown. After one day of psilocybin, what is seen is a decrease in within-DMN connectivity (responsible for the negative rumination) and an increase in DMN connectivity with other higher-order networks, including the EN and SN (responsible for switching and directing cognition externally). This is thought to be largely responsible for what is often referred to in studies as this global decrease in network modularity seen after ingestion of psilocybin.
The reason I have gone into this is that these findings suggest not only the potential psilocybin may have in the treatment of depression. But this decrease in network modularity and increase in flexibility may be important in the treatment of other disorders that are largely a result of this kind of cognitive inflexibility. Disorders such as OCD, autism, and others. The reason for this is that this decrease in network modularity by definition also involves an increase in the communication of these networks with other networks ordinarily outside of their community limits. But it is this communication which likely leads to the therapeutic change in the individual suffering with these diseased states. In a sense, it frees them up from a long-held pattern of excessive self-focus and rumination. A nice metaphor which explains this, which I read in another article pertaining to this, would be to compare the depressed brain to a landscape. And this landscape consists of these deep wells. These deep wells represent the rigid thought patterns characteristic of depression—and when in these thought patterns, both obscure the horizon but also impede the ability to alternate between different thought patterns. Psilocybin can almost be seen to flatten this landscape, allowing for broader perspectives and less rigidity in alternating between thoughts, and to extend the metaphor—this flatter landscape persists to various extents after treatment.
Psilocybin Administration
Because neuroplastic changes also occur in an experience-dependent manner, experiences people have during and around the treatment will have a greater psychological impact than they otherwise would. This is why the supplementation with psychotherapy alongside other considerations to the treatment setting is an essential part of the dosing protocol.
The majority of clinical trials have administered two separate doses at a dose of roughly 25mg, with each dose given roughly four weeks apart. The subjects either were seated or lay down, with an eye mask on (to avoid the distractions of visual hallucinations that may frequently occur with some). Music is also critical, specifically due to its effects on our emotional experience which is often more intense during a ‘trip’. Music protocol advised was to start calm, moving to a slightly more upbeat pace during the peak effects around two hours in, then tapering down to more calming music towards the end. The ‘trip' usually lasts around four to six hours. As it relates to the psychotherapy—generally, in the historic studies, the psilocybin-assisted psychotherapy protocol consists of pre-treatment, treatment, and post-treatment sessions. There were several conventional psychotherapeutic modalities mentioned, which were modified for use in psilocybin clinical trials: Most commonly used ones being CBT and existential psychotherapy. These conventional theories were almost always in the pre or post treatment sessions. During the treatment sessions, the therapists served as more of a guide, providing reassurance and gentle guidance if needed. The average number of pre-treatment sessions was around three, treatment sessions as previously mentioned usually two, and the number of post-treatment sessions around six.
So generally, with two doses of 25mg-30mg spaced a few weeks apart, with assisted psychotherapy, and the appropriate setting during treatment sessions—these are things that will maximise the efficacy that psilocybin can have.
Conclusion
That wraps up our exploration into the medications, both established and emerging, used in the treatment of depression. Please note that although I am a clinical doctor myself, I strongly advise against the self-administration of all of the medications and protocols mentioned above. This article is purely for educational purposes, serving as a useful resource to point each of you in the right direction when consulting with a specialist clinician in this area. If you want to learn more as it pertains to your specific circumstance, or that of loved ones, please also do not hesitate to reach out to myself.
Resources
Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder - PMC (nih.gov)
How do hallucinogens work on the brain? | BPS
Increased global integration in the brain after psilocybin therapy for depression | Nature Medicine
Psilocybin Rewires the Brain for People with Depression | UC San Francisco (ucsf.edu)
Analysis of Psilocybin-Assisted Therapy in Medicine: A Narrative Review - PMC (nih.gov)