In this symposium titled ‘Novel TAARgets for stabilizing neural circuits in schizophrenia’, presented at the 35th ECNP Congress in Vienna, Austria (15th−18th Oct), Prof Christoph Correll (The Donald and Barbara Zucker School of Medicine, New York, USA; Charite Universitätsmedizin, Berlin, Germany) first discussed how both positive and negative symptoms of schizophrenia involve widespread disruptions to a number of neural circuits linking the striatum, limbic system and cortex. Antipsychotics predominantly bind to D2 dopamine receptors and, while helpful for some symptoms, can be associated with a number of adverse events depending on their receptor action profile. Dr Anissa Abi-Dargham (Stony Brook University, UK) introduced trace amines, which are structurally similar to monoamines but function more diffusely, and trace amine receptors, that can heterodimerise with other receptors and influence their functioning. As these include the D2 dopamine receptors, Prof Leslie Citrome (New York Medical College, US) discussed how trace amine associated receptor (TAAR) targeting drugs are being in investigation in patients with schizophrenia and have shown significant changes in positive and negative symptoms with a low adverse event profile.
Targeting neural circuits in schizophrenia can help with unmet needs
Schizophrenia is currently understood to be a disorder of hyperactive dopamine at D2 receptors, hypofunction of the glutamate N-methyl-D-aspartate (NMDA) receptor and cortical hyperfunction of the serotonin 5-HT2A receptor. Changes in neural circuits include those in the mesocortical pathway, due to decreased dopamine and GABA release and 5HT2A expression; the mesolimbic pathway, associated with negative symptoms; the mesostriatal pathway, associated with increased dopamine synthesis and release and positive symptoms; and the nigrostriatal pathway, with motor involvement.1,2
Symptoms of schizophrenia involve complex brain circuitry and not just discrete regions
It was initially thought that positive symptoms of schizophrenia arose from abnormal functioning of dopamine projections from the midbrain to limbic regions. More recent work though, has shown far wider neurological connections between the striatum and both the midbrain and the cortex, involved in executive functions and sensory motor functions.3-6 Neuroimaging studies reveal that positive symptoms are linked to dopamine hyperactivity in a circuit starting at the dorsomedial substantia nigra and involving striatal associative and adjacent sensorimotor regions.2 One study in patients with schizophrenia found significant dopaminergic function increases in the sensorimotor and especially associative regions in the striatum.7 Striatal connections to other parts of the brain have also been shown altered in frontal areas linked to positive symptom severity.8 This, said Prof Howes, points to the striatum being one cause of the alterations in functioning in the cortex in patients with schizophrenia.
For over 70 years, dopamine D2 receptor blockade have been the treatment target for schizophrenia.1 However, around a third of patients do not respond to such antipsychotics, or have persistence of negative and cognitive symptoms.1 There are also a number of adverse events associated with antipsychotics related to their mechanism of action, which may result in drug non-adherence.9 Antipsychotic binding to D2 receptors10 affects the above mentioned pathways in a widespread manner and while mesostriatal pathway blockade may lead to a reduction of symptoms, blockage of other neural circuits, such as the mesolimbic and mesocortical pathways, may actually increase negative symptoms. Additionally, nigrostriatal pathway blockage is associated with myriad adverse events including tremor, rigidity, akinesia, dyskinesia and dystonia, with tuberoinfundibular hypothalamic pathway blockage associated with prolactin elevation, sexual dysfunction, amenorrhea and galactorrhoea.1,2
Trace amine-associated receptors (TAARs) as therapeutic targets for schizophrenia
What is needed, according to Prof Howes, are antipsychotics that are more selective to “turn down overactive dopamine but not block it where it’s functioning normally.” Such drugs in development include trace amine receptor compounds and muscarinic receptor agonists that do not directly interact with dopamine receptors.10,11
Trace amines have similar structures to monoamine neurotransmitters but are expressed at far lower levels and are not packaged and released as these neurotransmitters are. They function at trace amine-associated receptors (TAARs), the most characterised of which is TAAR1.12-15 TAARs occur in several parts of the brain involved in cognitive, emotive and motor circuits. These include the dorsal raphe nucleus; the ventral tegmental area (VTA) and substantia nigra; the hippocampus and subiculum; the globus pallidum; the basolateral amygdala; and several cortical areas.16 TAAR1 is also expressed in peripheral tissues including pancreatic b-cells, immune systems cells, the liver and the digestive system.12,14,15 This, postulated Dr Abi-Dargham, means trace amines may affect glucose metabolism, the immune response and gastric emptying.
Trace amines work in several brain regions and throughout the body
The TAAR1 receptor is located intracellularly in both pre- and post-synaptic neurons. It can move to the cell surface and heterodimerise with other receptors including D2 dopamine receptors, influencing their functioning.13 For instance, dopamine decrease in hyperdopaminergic regions, such as the nucleus accumbens can be decreased by TAAR1 agonists.12,15 TAARs also play a role in prefrontal cortex glutamate transmission with TAAR1 agonists shown to suppress non-competitive NMDA receptor blocker-induced hyperlocomotion. This occurs by preventing hypoglutamatergic activity.12,15 TAARs additionally have a role in balancing 5-HT receptor activity,12 as it has been evidenced in TAAR1 knockout mice that show increased serotonin levels13 and how TAAR1 activation can increase 5HT1A receptor agonist potency and TAAR1 blockade can decrease it.14,16 When the TAAR1 receptor is stimulated with an agonist, dopamine availability can be lowered via decrease in midbrain VTA dopamine neuron activity. TAAR1 agonists can also increase presynaptic D2 autoreceptor inactivation and reduce dopamine-driven behaviours post-synaptically.13,16
TAAR1 agonists as potential treatments for schizophrenia
There is a lot of preclinical evidence to support the development of TAAR1 targeting drugs in schizophrenia. This includes that some rare mutations show TAAR1 involvement in patients with schizophrenia and that TAAR1 knockout mice have dopamine increases, similar to that shown in schizophrenia. TAAR1 agonism in animal models also point to antipsychotic-, antidepressant- and pro-cognitive effects as well as prevention of weight gain and fat accumulation related to the use of some antipsychotics.12,15,17,18
TAAR1 agonists can lead to improvements in positive and negative symptoms of schizophrenia
Phase II and III studies have been carried out and/or are underway including of a TAAR1 partial agonist19 and a TAAR1 agonist with 5HT-1A agonist activity.20 One randomised, placebo-controlled, clinical trial in patients aged 18−40, who were predominantly male (around 64%) and white (around 81%) found Positive and Negative Syndrome Scale (PANSS) scores significantly decreased after 3 and 4 weeks’ treatment with a response rate (PANSS improvement ≥20%) of 64.6% with the TAAR1 agonist and 44.0% with the placebo. There were also significant effects on positive and negative subscales and on depression ratings.21 Improvements continued over 26 weeks follow-up.21,22 Adverse events included low incidences of somnolence, agitation, extrapyramidal symptoms and nausea with discontinuation because of an adverse event being 8.3% for the TAAR1 agonist and 6.4% for the placebo.21 There were also minimal changes in weight, metabolic indices and prolactin levels over 26 weeks.22
Educational financial support for this Satellite symposium was provided by Sunovion Pharmaceuticals, Inc.
Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.