Schizophrenia (A*) Flashcards

Question

A*: How long is the delay between administration of a neuroleptic and clinical effect? What might cause this effect?

Answer 1

- Despite causing relatively rapid changes to central dopamine transmission, neuroleptic drugs show a therapeutic latency of approximately 2-3 weeks. This challenges the classical idea of the dopamine theory, which posits that dopamine hyperactivity is the primary dysfunction in schizophrenia. - This suggests that the therapeutic action of neuroleptic drugs involves some form of neuroplastic change, as these processes are usually relatively slow and occur over a similar timescale to that of the therapeutic latency of neuroleptic drugs. - It has been shown that haloperidol, a commonly used D2 antagonist neuroleptic drug, induces changes to neuronal physiology and connectivity in the striatal indirect pathway (Sebel et al., 2016). This led to differential degeneration and reinforcement of corticostriatal networks following 2 weeks of drug exposure in mice, a process which has been suggested to be governed by L-type Ca2+ channels. This is not unlikely considering polymorphisms of L-type Ca2+ channels are associated with schizophrenia. - Elucidation of the mechanisms underpinning this remodelling process will help to explain the mechanism of action of D2 antagonists - the primary mode of treatment for schizophrenia. A clear understanding of these mechanisms will, in turn, facilitate the development of novel therapeutic targets.

Answer 2

Emerging glutamatergic drug treatments for schizophrenia (mention why potentiating glutamate transmission is useful - glutamate hypothesis): 1 - D-amino acids. - As described above, D-serine, although not yet approved for the treatment of schizophrenia, is thought to provide some efficacy for the cognitive symptoms of schizophrenia as a supplement to non-clozapine neuroleptics. It is generally well tolerated, however some studies indicate that byproducts of D-serine metabolism may cause nephrotoxicity (Maekawa et al., 2005). Also, D-cycloserine can be neurotoxic in high doses, limiting potential for treatment requiring high dosages. Sarcosine is associated with respiratory complications at high doses, and may also cause motor symptoms, again limiting options for treatment. The safety of glycine requires further investigation, but is currently thought to cause minimal / no side effects. 2 - GLYT1 inhibitors (e.g. sarcosine, as described above). GLYT1 is a reuptake transporter for glycine that transports glycine from the synapse into pre-and postsynaptic neurones, as well as glia. It facilitates the termination of glycine transmission at both NMDA receptors (where glycine is a coagonist with glutamate) and glycine receptors. Therefore, inhibition of GLYT1 postpones the termination of glycine at its receptors, thereby potentiating glutamate transmission. As described in A* card 24, sarcosine shows no / few side effects and good safety profiles. This is true for most GLYT1 inhibitors, although some have been shown to cause dizziness, requiring reduction of the administered dosage. 3 - EAAT3 inhibitors. - EAAT3 is a glutamate transporter that transports glutamate from the synapse primarily into neurones. Analogous to GLYT transporters for glycine, EAAT transporters terminate glutamate transmission at glutamate receptors. Hence, inhibition of EAAT increases synaptic glutamate, potentiation transmission at all types of glutamate receptor. Of particular interest in schizophrenia is the potentiation of NMDA receptors. 4 - mGlu2 and 3 agonists. - Mixed mGlu2/3 (group II metabotropic) agonists are thought to potentiate glutamate transmission at NMDA receptors containing the NR2B subunit. This effect has been shown to be mediated by suppressing GSK3 signalling, a signalling pathway which is known to be negatively associated with neurogenesis, neuroplasticity and neuroprotection (see depression lecture for details on signalling pathway). These drugs are also associated with restoration of physiological neurone morphology, such as forming dendritic spines, which are lost in some glutamatergic neurones in schizophrenia due to a defective pruning process. One prominent mGlu2/3 agonist, LY2140023, significantly improved both positive and negative symptoms of schizophrenia compared to a placebo in a phase II trial. However, the drug did not meet its primary efficacy endpoint, was associated with weight gain and convulsions and showed no improvement in extrapyramidal symptoms, and hence did not meet phase III trials. Today, the focus on targeting mGluRs has changed from orthosteric agonists to PAMs, as these only exert an effect when present with an endogenous agonist (and therefore show better safety profiles), generally show greater specificity for the receptor compared to orthosteric ligands (and therefore show fewer side effects) and have reduced potential for desensitisation.

Answer 3

- Purinergic hypothesis of schizophrenia: dysfunction in purinergic signalling results in a decrease in adenosine transmission which underlies the imbalance between glutamatergic and dopaminergic transmission (Lara and Souza, 2000). - The hypothesis posits that dysregulation of glutamatergic signalling arises from dysfunctional A2A receptor activity, which disrupts glutamate homeostasis through disturbed astrocyte-neurone signalling. - In mice models of schizophrenia, antagonism of neuronal A2A receptors is beneficial for cognitive function but antagonism of astrocytic A2A receptors is detrimental to cognitive function (Matos et al., 2015). - Purinergic miscommunication has been shown to lead to decreased presynaptic glutamate release, and downregulation of NMDA receptors. - The purinergic hypothesis also suggests that other neurotransmitters, such as 5-HT, noradrenaline, dopamine and acetylcholine become dysregulated due to defective purinergic signalling. Collectively, these physiological changes are thought to underlie both positive, negative and motor symptoms of schizophrenia. - Over the past decade, evidence has accumulated to suggest that stimulation of A2A receptors has potential to improve symptoms of schizophrenia. It is well-documented that A2A receptors form functional dimers with D2 receptors in the indirect striatal pathway of the basal ganglia. Here, A2A receptor activation antagonises D2 receptor function. Since schizophrenia is associated with dopaminergic hyperactivity, the therapeutic action of A2A stimulation in schizophrenia may be through attenuation of striatal dopaminergic transmission. - Stimulation of A2A receptors would, in theory, be particularly useful for treating positive symptoms of schizophrenia. That is, the presence of abnormal thoughts and behaviours such as delusions and hallucinations. In schizophrenia, hyperactivity of dopaminergic transmission at the striatal indirect pathway leads to a disinhibition of thalamus, which receives inhibitory innervation from the basal ganglia in what is known as the cortico-basal ganglia-thalamo-cortical loop. This, in turn, results in a decrease in thalamic sensory gating (opening of filter), causing positive symptoms. Indeed, the efficacy of A2A receptor stimulation has been evidenced in clinical trials: - Dipyridamole is an adenosine uptake inhibitor. Its primary function is as a vasodilator and anti-platelet drug, however is has also shown efficacy for the treatment of positive symptoms of schizophrenia as an adjuvant therapy (Wonodi et al., 2011). Although showing a good safety profile, dipyridamole is contraindicated in patients suffering from respiratory diseases since it is associated with increased risk of bronchospasm. Furthermore, the vasodilatory effect of dipyridamole effect makes it unsuitable for use in patients suffering from hypotension, and in geriatric patients, dipyridamole use is associated with increased risk of orthostatic hypotension. The ubiquity of A2A receptors makes diverse side effects an inevitable consequence of orthosteric agonism, hence the development of positive allosteric modulators (PAMs) of A2A receptors with high CNS penetrability will likely result in a preferable side effect profile. Various A2A PAMs have recently been discovered, however much of the research focus for these drugs has been directed towards inflammatory conditions.

Answer 4

1 - NAAG peptidase inhibitor ZJ43 reduces PCP-induced motor symptoms of schizophrenia. - NAAG is a partial agonist at NMDA receptors, meaning in low concentrations, NAAG has an antagonistic effect, and in high concentrations has an agonistic effect. In schizophrenia, it has been hypothesised that decreased expression of NAAG underlies the hypoglutamatergic state. This has been evidenced by functional imaging studies comparing NAA and NAAG expression in schizophrenia patients and healthy individuals. Furthermore, a negative relationship exists between NAAG expression and positive and negative symptoms scale (PANSS) (Jessen et al., 2013). Hence, ZJ43 is thought to improve symptoms of schizophrenia by reducing NAAG metabolism, which in turn alleviates NAAG-mediated inhibition of glutamatergic transmission at NMDA receptors. Also see below for general neuroprotective functions of NAAG. 2 - NAAG peptidase inhibitor 2-PMPA protects against neuronal apoptosis and neurite degeneration in diabetic neuropathy. - The mechanisms underlying the therapeutic effect of NAAG in diabetic neuropathy are unclear, however cell culture models of diabetic neuropathy have shown that mGluR activation leads to an increase in synthesis of NAAG, which in turn inhibits proapoptotic caspase enzymes. This could underlie the neuroprotective effect (and also see point 3 below). 3 - NAAG peptidase inhibitor 2-PMPA and GCPII inhibitors protect against motoneurone death in amyotrophic lateral sclerosis, a neurodegenerative disease characterised by motor deficits arising from degeneration of upper and lower motoneurones. - 2-PMPA: Owing to NAAG's neuroprotective effect, NAAG peptidase inhibitors have been proposed to have therapeutic potential for the treatment of neurodegenerative diseases such as ALS. NAAG is a potent agonist at mGluR3s. Activation of mGluR3s is known to reduce glutamate release through action at inhibitory mGluR3s, preventing excitotoxicity and stimulating release of growth factors such as TGF-beta that prevent neuronal apoptosis (and also see point 2 above). - GCPII inhibitors: This has a dual mechanism. Firstly, inhibition of GCPII leads to increased concentrations of NAAG, which as described above, exerts a neuroprotective effect. Secondly, NAAG is metabolised into NAA and glutamate. By inhibiting NAAG metabolism, glutamate concentrations decrease, protecting against excitotoxicity.

Schizophrenia (A*) Flashcards

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