Introduction:

In Medicine, the existing of more than one condition or disease is common and it is so called “Comorbidity”. This term by definition refers to the co-existence of two conditions without any relationship such as causal. In other word, comorbidity is the co-existing of two conditions in parallel with no relationship, or different pathophysiology and treatment paths. But in fact that is not the case in many situations, as one condition may give rise to another, or in a better sense, one is primary and the other is secondary. For example hypertension or high blood pressure can lead to stroke and its consequences such as hemiplegia, or diabetes as a primary condition could cause many complications as secondary conditions such as diabetic foot and poor vision, etc. The treatment of the primary condition such as diabetes or osteoporosis could prevent the secondary condition such as diabetic wounds and bone fractures.

 Although some of these co-conditions that are still commonly labeled as “comorbidity” are very obviously primary and secondary to each other with a causal or consequential relationship, some conditions specially in Psychiatry may not look that much related to each other. For example in ADHD, secondary conditions or complications such as depression, oppositional defiant and anti-social behaviours or disorders, substance use disorders, etc. while not much superficially related, they are in fact so, and treatment of ADHD would prevent majority of the others. For the first time, I coined the term “post-morbidity” in ADHD for these secondary conditions or complications that are still in the literature considered loosely “comorbidity” with no apparent causal relationships. (1-2)

 

A similar relationship exists between depression and anxiety that are commonly comorbid in psychiatry and it is still considered with no causal or temporal relationship as simply “comorbid” in the literature and among experts. If two conditions are causally related and not appreciated as such, it will affect their treatments and both conditions could be treated with two treatments, e.g. two or more medications. But if there is a causal relationship, the treatment of the primary condition would prevent and treat the secondary or “post-morbid” condition, while their pathophysiologic relationship is more appreciated and understood. In this paper, I will show for the first time that such a primary and secondary or “post-morbidity” relationship exists between depression and anxiety that has never to this date been recognized.

 

Depression and Anxiety: Are they related?

Depression in history is known longer than anxiety, from the time of antiquity, specially by the father of medicine, Hippocrates (460-370 BC) as “Melancholia”. But Anxiety despite always existing in humans and animals as “hypervigilance” and “fear” or “fight or flight” reactions, its history of recognition in the literature is much later and perhaps was first recognized in philosophy by Soren Kierkegaard in the “The Concept of Anxiety” in 1844, before its recognition by Freud and other psychoanalysts. (3) Sigmund Freud, originally a physician and neurologist, who was attracted by hypnosis of another neurologist, Charcot in France, and moved fully to psychology and psychoanalysis, at the beginning of the 20^th century recognized anxiety as a neurosis and the origin or mother of all psychiatric ailments. (4) This idea went so far that the later psychoanalysts such as Otto Rank, recognized even birth as “separation trauma” or anxiety. (5)

 Later on, melancholia was re-labeled as “depression” and into different types such as unipolar/bipolar; reactive/endogenous; typical/atypical and nowadays it is commonly known as “Major Depression”. But Anxiety as it is its nature to expand and generalize while it could be specified and encapsulated, is off different types, the common type being GAD (Generalized Anxiety Disorder), with other types such as Panic Diosrder, different phobias such as Agoraphobia, OCD (Obsessive Compulsive Disorder), and tic disorders among others. While speaking of depression it is commonly referred to “Major Depression” or “unipolar depression”, when it is spoken of Anxiety it is commonly referred to GAD or Generalized Anxiety Disorder.

 One simple way of understanding the temporal relationship between anxiety and depression is the age of onset of these common mood conditions. Despite DSM5, the bible of diagnostic classification of psychiatric disorders, citing the onset of depression earlier from adolescence to 20’s, and GAD or anxiety later on in 30’s, the clinical observation that matches early recording and writing on anxiety, specially in psychoanalysis refer to a much earlier onset in childhood. (6) The common anxiety and fear in childhood such as separation from parents or care givers, to fear of dark, being left alone, tics and other somatic symptoms of anxiety such as belly ache for school refusal, shyness and social anxiety, performance anxiety upon oral presentations, etc. all testament to an early onset of anxiety, than depression.

 Anxiety or GAD that manifests as tension, worries, anticipation of the worst, performance and social anxiety, and else could escalate to anxiety or panic attacks in some and generalizes into many situations. Over time anxiety that is very draining mentally, it will complicate by the development of depression in the individual that by now being in adolescence or early adulthood. While some parents or even children recognize their anxiety from early on in childhood and seek help, others for having milder condition or lack of recognition or resources, they will seek help later on in adolescence and adulthood. Unfortunately when comorbid with depression and sought for medical help, the temporal and causal relationship between anxiety and depression is often missed by the clinicians who would treat both at the same time, most commonly with an antidepressant in combination with a tranquilizer, mostly benzodiazepines such as Lorazepam or Ativan.

 Both anxiety and depression are commonly known to have similar if not the same pathophysiology, hence the same treatment for both with antidepressants with not much differentiation in between. While the neurotransmitters involved in our mood control or balance are the monoamines (Serotonin, Norepinephrine and Dopamine), GABA (Gama Amino Butyric Acid) and Glutmate, each have different functions on our mood and beyond that should not be treated the same. Even the existing antidepressants (that are so called for lack of a better term) their effects on the neurotransmitters are different and they are not all the same. For example, SSRIs (Specific Serotonin Reuptake Inhibitors) increase basically the level of serotonin in the brain, while SNRIs (Serotonin & Norepinephrine Reuptake Inhibitors) increase the level of both serotonin and norepinephrine in the brain, while dopaminergic antidepressants such as Wellbutrin or Bupropion mostly increase the level of dopamine in the brain, and benzodiazepines increase the level of GABA that is an inhibitory neurotransmitter in the brain.

As it is demonstrated in the above and below diagrams, anxiety is more localized neuroantomically and neurochemically in the mid-brain and through HPA axis to the cortical modulation of serotonin. But depression is a more generalized pathophysiology of mood balance, involving the whole middle, limbic and cortical regions of the brain, hence more neurotransimtters, and neuromodulators beyond serotonin.

The neuroanatomic pathway, hence the neurochemical underpinning of anxiety (that is more an internal feeling without the existence of an external fearful stimulus) like fear involves the middle brain including Amygdala, HPA (Hypothalamic-Pituitary-Adrenal) axis in the addition to the cortical neuromodulator role of serotonin, as we see in the diagram below. (7-8)  

 

In case of depression, more than one neuroanatomical pathway and more than one cortical neurotransmitter are involved as we see in the following images. (9)

 

While serotonin could be considered as the main neurotransmitter in the control and balance of the mood, it is mostly reduced in anxiety and anxiety disorders. That is why SSRIs, e.g. the strongest and most specific ones such as Escitalopram controls the anxiety, GAD and panic disorder the best. While serotonin having more calming effect on the mood and its deficiency could cause anxiety from an early age, Norepinephrine has a mood uplifting, motivating and energizing effect on the mood, so SNRIs, specially the Levomilnacipram that holds twice increasing effect on Norepinephrine than Serotonin, has an uplifting, motivating and energizing effect on the individual. Dopamine that controls the physical aspect of the mood and its deficiency could cause psychomotor slowness in some depressions, could be helped the best with dopaminergic antidepressants such as Wellbutrin or Bupropion. GABA for being the most abundant neurotransmitter of the brain, released from the Glia cells that glue the neurons together, has a generalized calming effect on the brain and mood. That is why tranquilizers such as benzodiazepines and alcohol have a generalized, not specific calming effect, mostly but temporarily beneficial for anxiety and panic, though causing dependency and in long-term use, rebound anxiety.

As we see in the above diagram, there is a distinct difference in the degree of involvement and release of common neurotransmitters between depression and anxiety. Also as we see in the diagram below, there is a closer connection between Norepinephrine and Dopamine in synthesis, than serotonin that has a different synthetic pathway from L-Tryptophan.

Moreover there is a balance between all the neurotransmitters in the control of the mood, specially among the three monoamines of Serotonin, Norepinephrine and Dopamine, so that the change in the level of one would affect the others. Therefore SSRIs that specifically increase the level of serotonin in the brain, specially over time could dampen the effect and level of the other two monoamines, norepinephrine and dopamine. (10) That is why after long-term or even short-term use of SSRIs, the side-effects of fatigue, forgetfulness and other cognitive impairment and sexual dysfunctions are common. Despite all the antidepressants are used equally and are all indicated with not much differentiation in the treatment of anxiety and depressive disorders, SSRIs due to their specificity in increasing the level of serotonin are the best current medical treatment for anxiety, while SNRIs specially the ones with more norepinephrine effect such as Levomilnacipram are better treatments for depression.   

                

Moreover in anxiety and fear due to their defensive and survival nature of fight or flight reaction, norepinephrine more than any other neurotransmitters such as serotonin, has a tonic and phasic manners of release. While there is a consistent tonic release of norepinephrine as baseline for alertness, vigilance and else, at the time of provocation in anxiety and fear, there will be an upsurge phasic release in response to stress and real or perceived danger. (11-12)

 

Conclusion:

In summary, anxiety as it is very common and innate in the nature even in animals for defense and survival as vigilance, it is also so in humans with an early onset in childhood. Therefore in cases where both anxiety and depression coexist, one specially the clinicians need with a through history and discovery, elucidate the early onset of anxiety as the primary condition that later on has been complicated with depression. The importance of this differentiation is vital in the treatment strategies as the successful treatment of the anxiety with a specific serotonergic agent or antidepressant or SSRIs such as Escitalopram or Vortioxetine would treat the post-morbid depression as well. Moreover and along this pathophysiologic concept, the treatment of depression without a long-standing anxiety is better achieved by an SNRI, specially the one with more norepinephrine effect, such as Levomilnacipram. Therefore despite the claims of all antidepressants making pharmaceutical companies and despite the approval of all these for different indications by the health authorities such as FDA, all antidepressants are not the same and have differential effects and need to be prescribed by clinicians more diligently and scientifically.  

Dr.Mostafa Showraki, MD, FRCPC                                                                  Lecturer, School of Medicine, University of Toronto,Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”

 Reference:

1. Showraki M. ADHD:Revisited. 2013. Kindle Books. Amazon.
2. Showraki M. adhdrevisited.com.
3. Søren Kierkegaard The Concept of Anxiety: A Simple Psychologically Orienting Deliberation on the Dogmatic Issue of Hereditary Sin June 17, 1844 Vigilius Haufniensis, Edited and translated by Reidar Thomte Princeton University Press 1980 Kierkegaard’s Writings, VIII
4. Freud, Sigmund and Bonaparte, Marie (ed.). The Origins of Psychoanalysis. Letters to Wilhelm Fliess: Drafts and Notes 1887–1902. Kessinger Publishing, 2009.
5. Rank, Otto; Lieberman, E. James (1993). The Trauma of Birth. New York: Dover Publications.
6. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington,VA: American Psychiatric Association. 2013.
7. Curran KP, Chalasani SH. Serotonin circuits and anxiety: what can invertebrates teach us? Invertebrate Neuroscience. 2012;12(2):81-92.
8. Martin EI, Ressler KJ, Binder E, Nemeroff CB. The Neurobiology of Anxiety Disorders: Brain Imaging, Genetics, and Psychoneuroendocrinology. The Psychiatric clinics of North America. 2009;32(3):549-575.
9. Dale E, Bang-Andersen B, Sánchez C. Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. Biochem Pharmacol. 2015 May 15;95(2):81-97.
10. Trivedi MH, Hollander E, Nutt D, Blier P. Clinical evidence and potential neurobiological underpinnings of unresolved symptoms of depression.J Clin Psychiatry 2008; 69: 246-258.
11. Howells FM, Stein DJ, Russell VA. Synergistic tonic and phasic activity of the locus coeruleus norepinephrine (LC-NE) arousal system is required for optimal attentional performance. Metab Brain Dis. 2012 Sep;27(3):267-74.
12. Tejani-Butt S, Kluczynski J, Paré WP. Strain-dependent modification of behavior following antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Feb;27(1):7-14.