The neurobiology of treatment-resistant depression

Introduction

Multiple treatment modalities are effective for major depressive disorder (MDD), including medications, certain psychotherapies, and brain stimulation approaches such as electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS). However, treatment resistance, that is lack of full symptom remission after one or more rounds of antidepressant treatments of adequate dose and duration, is the rule, not the exception with MDD ( ). For example, the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was a large trial that treated depressed patients across four treatment steps, beginning with citalopram monotherapy ( ). Only about one-third of patients remitted with initial treatment with citalopram, and another third to second-level treatments with either monotherapies, combinations of medications, or combined citalopram and cognitive behavioral therapy. By the third and fourth steps, only 13.7% and 13% of patients remitted, respectively. The cumulative remission rate was only 67%, and over half of remitted patients relapsed during a 12-month naturalistic follow-up phase ( ). Clearly, something is preventing response in many people and causing others to relapse. The purpose of this chapter will be to address the neurobiological impediments to antidepressant treatment response.

Why do people get depressed?

Allostasis is the normal physiological adaptation to maintain homeostasis in face of stressors ( ; ). The cumulative effect of stress on the body is referred to as allostatic load ( ). The responses to threats of homeostasis, such as activation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, and cytokine responses are adaptive in the short-term ( ). In fact, short-term stressors that are perceived to be controllable have a positive effect on brain health, enhancing cognitive and physical performance ( ). However, chronic allostatic loading is harmful and is associated with a range of conditions, including abdominal obesity, hypertension, diabetes, cardiovascular disease, arthritis, and depressive symptoms ( ; ; ). Persistent activation of endocrine, cardiovascular, metabolic, and emotional responses increases risk for and progression of disease ( ). Brain allostatic loading is a known factor in depression ( ). For example, found that several aspects of allostatic responses, including HPA activity, immune response, anabolic activity, and cardiovascular disease, were associated with depressive symptoms, after adjusting for demographic, socioeconomic, and other health-related factors in older adults. How, then, does that lead to depression?

Much work over the last two decades has focused on the dynamic regulation of neuronal dendrites, spines, and synapses in brain, collectively referred to as neuroplasticity. Spines are protrusions from dendrites that form synapses with other cells ( Fig. 4.1 ). A single neuron can have thousands of spines and synapses. These change very dynamically in response to environmental cues. The formation, maintenance, and regression of spines and synapses is regulated by a wide range of factors; chief among these are neurotrophins such as brain derived neurotrophic factor (BDNF) and related trophic factors such as insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) ( ). Interestingly, acute stress that is short-term and controllable actually increases BDNF along with spines and synapses ( ). However, chronic, unpredictable, and uncontrollable stress reduces BDNF synthesis and release and regression of dendrites and spines, a process that is associated with depression-like behavior in animal models ( ).

The effects of stress on the brain are complex and vary by region. For example, stress and glucocorticoids result in regression of dendrites and loss of dendritic spines and synapses in hippocampus and frontal cortex ( ). Conversely, acute stress increases spines, and chronic stress leads to enlargement of dendrites in the basolateral amygdala ( ). However, the net loss of synapses in frontal cortex and hippocampus, particularly those connecting pyramidal and other neurons with interneurons, appears to underlie depression.

The process of removal of synapses, spines, and dendrites is a type of macroautophagy, usually just referred to as autophagy, which is an adaptive process by which cells remove components. A structure called a phagophore engulfs cellular material forming an autophagosome, which merges with a lysosome, resulting in the degrading of proteins. Various types of cell stress, including toxins, microorganisms, metabolic stress, and ischemia, activate autophagy, resulting in the clearing of damaged proteins or cell remodeling ( ). This process is tonically suppressed by the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1), discussed in greater detail below. A variety of metabolic factors can suppress mTORC1 activity, releasing the autophagic process and leading to loss of spines and synapses ( ). Therefore, maintaining mTORC1 activity is critical in preserving spines and synapses.

Interneurons serve as functional regulators of pyramidal and related neurons (referred to as principal neurons), which mediate communication both within and between brain regions. Some types of interneurons release gamma-aminobutyric acid (GABA), the principal inhibitory transmitter in the nervous system, which functions as a key regulator of brain activity by “gating” both input and output of principal neurons ( ). Glutamate is the main excitatory output transmitter of principal neurons, which is balanced by GABA. Chronic stress and the depressed state that results from stress involve loss of GABA synapses on principal neurons and an imbalance in input and output. This excitatory (glutamate) to inhibitory (GABA) imbalance occurs because of a reduction in principal neuron dendrites, spines, and synapses ( ; ). A result of stress is a loss of inhibitory control by GABA interneurons.

BDNF and other trophic factors increase dendritic volume and density, and lead to the formation of spines and synapses. It also induces cell replication of neurons in the hippocampus (neurogenesis) ( ). However, continued input by BDNF is also required for the maintenance of dendrites, spines, and synapses. Chronic stress and the resulting depression-like behaviors in rodents are associated with reduced synthesis and release of BDNF, which results in progressive loss of spines and synapses ( ). Antidepressant treatments appear to reverse this process and increase BDNF activity. The binding of BDNF to TrkB initiates a cascade of intracellular signaling molecules that ultimately activate mTORC1 ( Figs. 4.1–4.3 ) ( ). The complex consists of the mTOR protein itself, along with regulatory-associated protein of mTOR (Raptor), and mammalian lethal with SEC13 protein 8 (nLST8). Proline-rich AKT1 substrate 40 kDa (PRAS40) interacts and activates mTORC1 following phosphorylation by RAC-alpha serine/threonine-protein kinase (AKT). AKT also inhibits the TSC1/2 protein complex and inhibitor of mTORC1 ( Fig. 4.3 ). mTORC1 regulates the synthesis of proteins, including those that form spines and synapses ( ). Stress inhibits this process in part by increasing cortisol which binds to the glucocorticoid receptor (GR) and inhibits mTORC1 ( ). Under normal circumstances, mTORC1 counterbalances this by inhibition of GR gene transcription. However, high or chronic stress unbalances this system resulting in reduced mTORC1 activity. Activation of the BDNF–TrkB–mTORC1 pathway leads to the genesis and maintenance of dendrites, spines, and synapses. Stress counters this by inhibition of both BDNF and mTORC1. As we will see below, antidepressant treatments help to restore BDNF and mTORC1 activity, leading to normalization of dendrites, spines, and synapses ( Fig. 4.2 ).

How do antidepressant treatments work?

Antidepressant treatments work by widely divergent proximal mechanisms—contrast, for example, the effects of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS). However, the net effect of most or possibly all effective antidepressant treatments is to increase the activity of trophic factors, particularly BDNF and its receptor tyrosine receptor kinase B (TrkB) (also known as tropomyosin receptor kinase B) ( ; ). Direct injections of BDNF and other trophins like neurotrophin- 3 have antidepressant-like effects in animal models of depression when injected directly into the brain ( ). Inhibition of BDNF ( ), TrkB ( ), or mTORC1 ( ) as well as other trophins like IGF-1 ( ) and VEGF ( ) block the effects of antidepressant treatments. Moreover, a series of studies indicated that depressed patients have lower BDNF levels prior to treatments, which increase after treatment ( ). However, antidepressant medications such as SSRIs do not directly affect these factors. How, then, do they produce effects on trophins and related molecules?

Fig. 4.2 illustrates the complex mechanisms of action of standard antidepressant treatments, focusing on the actions of SSRIs. Tryptophan (TRP) is taken up into the presynaptic neuron and is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase (TPH) (primarily TPH2 in brain). 5-HTP is converted to 5-HT by aromatic amino acid decarboxylase (AAAD). Free 5-HT is taken up into presynaptic vesicles by vesicular monoamine transporter 2 (VMAT2). The vesicles merge with the plasma membrane, releasing 5-HT into the synapse. There is a similar process with norepinephrine (NE), which is required by many antidepressant drugs. The NE precursor amino acid tyrosine is taken up by the presynaptic neuron and converted initially to l -DOPA by tyrosine hydroxylase (TH), then to dopamine (DA) by AAAD, and finally to NE by dopamine beta hydroxylase (DBH) (Fig. 4.2) . The vesicles merge with the plasma membrane, releasing 5-HT into the synapse. There is a similar process with norepinephrine (NE), which is required by many antidepressant drugs. The NE precursor amino acid tyrosine is taken up by the presynaptic neuron and converted initially to L-DOPA by tyrosine hydroxylase (TH), then to dopamine (DA) by AAAD, and finally to NE by dopamine beta hydroxylase (DBH). DA and NE are also taken up into vesicles by VMAT2 and released into the synapse.

5-HT binds to receptors that activate adenylate cyclase, which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cyclic AMP) through several 5-HT receptors (5-HT ₄ , 5-HT ₆ , and 5-HT ₇ ). SSRIs block 5-HT reuptake, which increases 5-HT interactions with postsynaptic receptors (Fig. 4.2) . Activation of the 5-HT receptor leads to coupling with a guanine nucleotide-binding protein (g-protein) which, in turn activates adenylate cyclase, producing cyclic AMP. The latter then interacts with protein kinase A (PKA), which releases its catalytic subunit (C), which phosphorylates the transcriptional factor cyclic AMP response element binding protein (CREB). Similar downstream effects can occur with 5-HT binding to receptors that activate phospholipase-C (PLC) ( ) (e.g., the 5-HT ₂ family of receptors), which catalyzes the conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol triphosphate (IP3) and diacylglycerol (DAG). The latter activates protein kinase C, which phosphorylates CREB. Drugs that increase synaptic NE have similar actions via NE beta-2 receptors that are also positively coupled to AC ( ). Phosphorylated CREB then translocates to the nucleus where it binds to a DNA enhancer region called a cyclic AMP response element (CRE) in the promoters of specific genes. This increases the transcription of a wide range of genes, including those coding for BDNF, TrkB ( ; ; ), and VEGF ( ). This system is also affected by other trophins such as NT-3 ( ) and IGF-1, which increase CREB phosphorylation ( ). The downstream effects of antidepressants on BDNF and other trophic factors appear to be required to normalize the reduced dendrites, spines, and synapses in the depressed brain and restore normal mood ( ). Other effective antidepressant treatments such as ECT ( ) and rTMS ( ) also affect BDNF, TrkB, and other trophic elements.

Cells maintain homeostasis through the balance of activating and inhibiting processes. While the effects described above are occurring, there are counteracting elements that dampen cell signaling. For example, when NE or 5-HT transporters are blocked, the transmitters not only bind to postsynaptic receptors, but also to presynaptic autoreceptors: NE alpha-1, and 5-HT 1A (5-HT _1A ) and 1B (5-HT _1B ) receptors ( ). These inhibit the release of NE and 5-HT respectively. Although these receptors do eventually downregulate with time, they slow the actions of antidepressants. Blier and colleagues ( ) conducted a series of experiments, first in rodents and then in human with the 5-HT _1A antagonist pindolol showing that it prevented the acute reduction in 5-HT release seen after short-term administration of SSRIs and accelerated the antidepressant response. The postsynaptic receptors coupled to the effector mechanisms described above (e.g., adenylate cyclase) downregulate after repeated activation by neurotransmitters by internalization (called receptor trafficking), making them vulnerable to degrading enzymes ( ), and by uncoupling from g-proteins. In addition, there are a large number of enzymes within neurons that metabolize or inhibit the elements described earlier. For example, there are enzymes that degrade drugs, proteins, and transmitters. Others inhibit protein action through the process of either phosphorylation (i.e., adding a phosphoryl group [P ⁺ O ₃ ^{2 −} ]) at serine, threonine, or tyrosine amino acids in proteins, or dephosphorylation. A well-known example of the latter is the inactivation of cyclic AMP by phosphodiesterases, but there are many other instances. These compensatory mechanisms maintain homeostasis in the cell but work against the mechanisms of action of standard antidepressants.

There are mechanisms of action of standard antidepressants that extend beyond uptake blockade. These effects include acting as antagonists of 5-HT _2A (mirtazapine, trazodone, nefazodone, and the atypical antipsychotics), 5-HT ₃ (mirtazapine, vortioxetine, and the atypical antipsychotics clozapine and olanzapine), 5-HT ₇ (vortioxetine) receptors, and acting as partial agonists (nefazodone, buspirone, vilazodone, and the atypical antipsychotics aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, and ziprasidone) or full agonists (vortioxetine) of 5-HT _1A . These effects confer anxiolytic- and antidepressant-like effects in animal models. Some of these effects appear to be direct, perhaps not involving neurotrophic actions. For example, acute activation of 5-HT _1A , or blockade of 5-HT _2A in the amygdala produces robust anxiolytic effects. In other instances, the effects are similar to the ones described for uptake inhibitors earlier. For example, activation of 5-HT _2A receptors inhibits BDNF mRNA synthesis, which is reversed with 5-HT _2A selective antagonists ( ). Therefore, some of the antidepressant effects of these mechanisms may depend on a downstream neurotrophic response.