New and emerging approaches to treat psychiatric disorders

Abstract

Psychiatric disorders are highly prevalent, often devastating diseases that negatively impact the lives of millions of people worldwide. Although their etiological and diagnostic heterogeneity has long challenged drug discovery, an emerging circuit-based understanding of psychiatric illness is offering an important alternative to the current reliance on trial and error, both in the development and in the clinical application of treatments. Here we review new and emerging treatment approaches, with a particular emphasis on the revolutionary potential of brain-circuit-based interventions for precision psychiatry. Limitations of circuit models, challenges of bringing precision therapeutics to market and the crucial advances needed to overcome these obstacles are presented.

Fig. 1 |. Brain targets for selective pharmacotherapeutics.

Major circuits and neurotransmitter pathways that are disrupted in a wide range of psychiatric disorders and that represent targets for treatment, based on extant knowledge. a, The DMN is a major intrinsic circuit involved in self-reflective processes and defined by functional connectivity between regions in the anterior medial prefrontal cortex (amPFC), the posterior cingulate cortex (PCC) and the angular gyrus (AG) within the parietal cortex. Default mode connectivity implicates excitatory glutamatergic (yellow) and inhibitory GABAergic (blue) neurotransmitter pathways. b, The negative affect circuit is engaged by negative emotional stimuli such as threat and sadness and is involved in reactions to these stimuli, the experience of the emotional states that they induce and regulation of these reactions and experiences. Key regions are the amygdala (Amyg), the anterior insula (A. insula) and the ACC, encompassing the subcallosal cingulate cortex (SCC), also referred to as the subgenual anterior cingulate cortex. It is modulated by serotonergic neurotransmitter pathways (green). c, The positive affect circuit, also known as the reward circuit, is engaged by responsiveness to socially rewarding stimuli, learned rewards, anticipation of these stimuli and the motivation to expend effort to obtain such rewards. Key regions are the VS, encompassing the nucleus accumbens, the medial orbitofrontal cortex (mOFC) and the ventral medial prefrontal cortex (vMPFC). These corticostriatal regions of positive affect circuitry interdigitate with mesolimbic dopamine pathways (purple). d, The cognitive control circuit is engaged by higher cognitive functions such as working memory and is required to inhibit task-irrelevant responses under task demands. Cognitive control circuitry is centered on regions of the DLPFC and the dorsal ACC (dACC) and implicates, among others, dopaminergic, GABAergic, glutamatergic and noradrenergic (not shown) neurotransmitter pathways.

Fig. 2 |. Brain-stimulation techniques and mechanism of action.

In rTMS, a rapidly alternating magnetic field is used to induce a secondary electric field 2–4 cm deep in the cortical tissue, directly activating cortical neurons. The standard ‘figure eight’ coil is shown. In tDCS, a weak current (1–2 mA) is applied continuously to the scalp for 20–30 min, increasing (anodal tDCS) or decreasing (cathodal tDCS) excitability of the underlying cortical tissue. In ECT, an electric current is passed through the brain to safely induce a seizure while a patient is under general anesthesia. A standard course may include 12 ECT sessions over the course of 1–2 months. In DBS, electrodes are surgically implanted directly into the target brain structure, and stimulation is regulated by a pulse generator placed under the skin in the chest wall. Stimulation intensity, pulse width, frequency and polarity can be programmed to optimize clinical response. Standard continuous high-frequency stimulation may inhibit neuronal activity locally while activating inhibitory presynaptic terminals and axonal activity. The mechanism of action for brain stimulation (inset) remains incompletely understood but is hypothesized to be similar across modalities. It may change network activity, connectivity and phase-amplitude coupling, disrupt pathologic oscillations, induce neuroplasticity, neurogenesis and angiogenesis and alter inflammatory mediators.

Fig. 3 |. Inflammation as a therapeutic target in psychiatric disease.

There are many points along the pathway from the immune system to the brain that can serve as therapeutic targets. External and internal environmental factors can activate peripheral blood immune cells, which then undergo metabolic reprogramming that involves a shift from energy-efficient oxidative phosphorylation (OXPHOS) to energy-expedient glycolysis, allowing rapid growth and proliferation, supported by increased fatty acid (FA) and amino acid (AA) synthesis. Activated immune cells in turn produce inflammatory cytokines including tumor necrosis factor (TNF) that can increase permeability of the blood–brain barrier by inhibiting production of claudin 5, a key protein in blood–brain barrier integrity, thus allowing direct access of inflammatory cytokines to the brain, produced in part by immune cells trafficking to perivascular spaces in the brain and the meninges. Once in the brain, inflammatory cytokines can decrease availability and release of dopamine in basal ganglia (for example, the striatum), while increasing the excitatory amino acid glutamate, whose activity may be further enhanced by activation of the kynurenine pathway. Altered neurotransmitter metabolism affects multiple brain regions, leading to disruption of neurocircuits that regulate motivation and motor activity (black arrows) as well as sensitivity to threat and loss (red arrows). These circuit-based behavioral biases in turn contribute to symptoms of anhedonia, psychomotor slowing and anxiety, arousal and alarm. IL, interleukin; CRP, C-reactive protein; SMA, supplementary motor area.