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Schizophrenia today: treatment developments

Despite improvements in treatment, challenges warrant continued development of novel therapeutic approaches for schizophrenia
Rebecca Schennach MD
Richard Musil MD
Michael Riedel MD
Hans-Jürgen Möller MD
Dept of Psychiatry Ludwig-Maximilians-University, Munich, Germany  
Despite significant improvements in the treatment of schizophrenia over the past few decades, a number of challenges exist today warranting the continual development of novel therapeutic approaches. This article aims to provide an overview of current developments in the treatment of schizophrenia.
Schizophrenia today 
Schizophrenia is a severe psychiatric illness typically arising during adulthood and leading to significant social and occupational impairments. Hallmark symptoms of the illness are delusions and hallucinations, disorganised thought (referred to as positive symptoms) as well as emotional flattening, poverty of speech and lack of energy (referred to as negative symptoms). The underlying pathophysiology and neurobiology of the  symptoms of schizophrenia have been the focus of research for over a century, and even though the definitive pathology remains elusive, today several neuroanatomical, neurochemical and genetic deviations have been established. Regarding the treatment of schizophrenia, it is important to state that, despite significant improvements in psychopharmacological developments in recent decades, residual symptoms still persist for many patients suffering from schizophrenia. However, remission of symptoms as well as personal recovery have emerged as treatment goals in modern psychiatry, warranting novel treatment approaches to further improve acute as well as long-term outcomes.(1) This review aims to provide an overview of current developments in psychopharmacological, neuromodulational and psychotherapeutic treatment strategies.
Developments in psychopharmacology 
Traditionally, schizophrenia patients are treated with antipsychotic compounds based on the dopamine hypothesis, which theorises that there is an increased production of this neurotransmitter or an over-sensitivity of dopamine receptors in certain brain regions. The blockade of dopamine receptors is the main mechanism of antipsychotic action. Today, atypical antipsychotics are the treatment of choice, given their low to minimal risk for extrapyramidal symptoms.(2)
Some of the antipsychotics recently licensed follow the concept of multi-receptor compounds with some specific alterations. It is currently unknown whether these antipsychotics will provide the progress expected in the field of schizophrenia treatment, such as improvement in cognitive domains and especially with regard to negative symptoms. However, improvement of negative symptoms has been reported for asenapine, the latest atypical antipsychotic. Owing to the fact that the majority of today’s marketed atypical antipsychotics are now off-patent, the antipsychotic market will become largely generic. New drug candidates currently under development need to demonstrate significantly differentiated pharmacological as well as safety profiles in order to become commercially viable. In the case of bifeprunox – a compound with partial agonist activity at dopaminergic D2, D4 and serotonergic 5-HT1A receptor and antagonism at D3 receptors – which showed some promising advantages, for example, reduction in weight and reduced cholesterol levels, further development was not authorised because it failed to obtain approval from the US Food and Drug Administration (FDA) due to lack of sufficient clinical efficacy. This underlines the long-winded and challenging process of drug development.
Currently, multi-receptor approaches are the aim, because they combine different receptor subtypes as either full antagonists or partial agonists. In addition to the traditional transmitter systems of dopamine and serotonin, other mechanisms under focus include the cannabinoid system, the neurokinin system, the glutamatergic system, the muscarinergic system and the melatonergic system – the latter for the treatment of cognitive deficits (for a summary see Table 1). The most promising recent approaches in the development of novel drugs will be discussed now in more detail.

Glutamatergic receptors
Glutamate is the primary excitatory neurotransmitter in the brain and disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia. One hypothesis of glutamate’s involvement in schizophrenia is that, early in the illness, excessive glutamate activity leads to excitotoxicity, which might possibly interfere with normal neurodevelopmental processes. The effects of glutamate are exerted by the activation of two distinct types of receptor: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs).(3)
NMDA receptors (glycine agonists)
Today it is widely accepted that the N-methyl-D-aspartate receptor (NMDA) featuring a modulatory co-agonist glycine-B site is hypofunctional and involved in processes leading to hallucinations, negative symptoms as well as cognitive impairments in schizophrenia. The NMDA receptor is considered to be a relevant target for antipsychotic and pro-cognitive effects. However, due to severe side-effects when directly antagonising NMDA receptors, strategies to enhance glycine-B site occupancy through glycine transporter 1 (GlyT1) blockade have been developed. The blockade of the glycine transporter raises the glycine level in the synaptic cleft and was associated with antipsychotic and procognitive efficacy in rodents.(4)
mGluR receptors
The second class of glutamate receptors regulates neurotransmission at glutamate synapses. Compounds acting as agonists at presynaptic mGluR2 and mGluR3 (group II) autoreceptors may reduce glutamate release and with it work neuroprotectively. One of the first compounds modulating glutamatergic receptors was LY354740, reversing ketamine-induced impairments of working memory in healthy participants. However, owing to low bioavailability in humans and poor brain exposure, the development of this drug was not pursued. In the meantime, there are several compounds showing antipsychotic effects in animal models and also a positive association between schizophrenia and the GRM3 gene, encoding mGluR3, as a candidate gene. Just recently, first results from a randomised clinical study have found a significant effect of LY2140023 on positive as well as negative symptoms of schizophrenia,(5) making this a very promising new treatment approach.
Selective NK3 antagonists 
Neurokinins are peptide neurotransmitters that comprise, among others, substance P, neurokinin A and neurokinin B. These transmitters respond to three different receptors in the CNS: neurokinin-1 (NK1), neurokinin-2 (NK2) and neurokinin-3 (NK3), expressed in the cortex, amygdala, hippocampus and mesencephalic structures, respectively. NK3 receptors are expressed on dopaminergic neurons and a potential antipsychotic effect has been postulated by NK3 antagonists by the reduction of dopaminergic and serotonergic tones. Two structurally different NK3 compounds – osanetant and talnetant – have been researched in more detail. Osanetant was reported to be effective against positive symptoms with similar efficacy to haloperidol, and talnetant was found to convert the typical properties of haloperidol to a more atypical profile. A low incidence of side-effects was found in both drugs. However, despite promising results, no further developments of either drug have been reported, which begs the question of whether development and clinical research have been continued.(6)
Phosphodiesterase 10A inhibition (PDE10A) 
Phosphodiesterases are intracellular enzymes with PDE10A having the most restricted distribution in the putamen and caudate nucleus in the mammalian striatal complex. It is believed to regulate the striatal output by effecting the cAMP and cGMP signalling cascades; because of this unique distribution, it may influence both the dopaminergic and glutamatergic pathways in a mechanistically novel approach in the treatment of schizophrenia. Animal models showed PDE10A to be effective in ameliorating certain psychotic phenomena such as locomotor hyperactivity. Currently, a selective PDE10A (called MP10) with an encouraging pharmacokinetic profile is in development, and still undergoing clinical evaluation.(7)
Additionally, besides the development of novel drug targets, different add-on strategies are evolving in order to enhance antipsychotic efficacy. Among others, different antidepressants are being evaluated with particular focus on reducing the negative symptoms or possible proneurocognitive effects of these compounds. Also, the application of cannabinoid receptor antagonists as well as the use of anti-inflammatory medications has shown initially promising results, with superior therapeutic effects as compared to placebo. 
Developments in neuromodulational therapies
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method with excellent tolerability and safety, which involves stimulation of specific brain regions. Using a stimulator coil placed on the scalp, a time-varying magnetic field is generated; rapid switches in the magnetic field induce an electrical current, which causes membrane depolarisation and neural activation. From studies that suggest an association between hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and level of negative symptoms, it has been hypothesised that rTMS applied to this brain area would reduce persistent negative symptoms. However, only modest effects have been observed to date with the most encouraging results wtih high-frequency stimulation. In treatment of hallucinations, slow rTMS is usually used because it supposedly reduces brain excitability when the coil is placed over the relevant brain areas (temporoparietal cortex). Average-to-good results using rTMS in auditory hallucinations were reported in several meta-analyses.(8)
Given that the effectiveness and sustainability of rTMS are still under debate, further stimulation techniques are currently being researched. It is believed that burst stimulation is a more powerful activator than tonic firing and that different stimulation sessions (at frequencies of 5Hz = theta, 10Hz = alpha or 20Hz = beta) might increase treatment benefits. Bilateral stimulation and prolonged treatment are under discussion, with a view to improving and extending the therapeutic effect. Only limited long-term studies of rTMS exist, which has hampered clear recommendations on the usefulness and long-term effects of maintenance rTMS treatment. Case reports, however, suggest that maintenance treatment is successful in patients with auditory hallucinations. Recently, to optimise treatment efficacy and target more precisely the relevant neuroanatomical structures involved in auditory hallucinations, MRI and fMRI have been used in rTMS treatment. Initial studies reported positive findings and a decrease in severity and frequency of auditory hallucinations in eight of 11 patients.(9)
Besides these attempts to improve the efficacy of rTMS, there is a growing discussion on the use of deep brain stimulation (DBS) in patients suffering from schizophrenia. Generally, DBS is a unique and promising method for patients with therapy-resistant psychiatric symptoms and favourable results have been reported for patients suffering from Tourette’s syndrome, obsessive-compulsive disorder and major depression, with no harmful effects reported so far. The exact neurobiological mechanism of the efficacy of DBS is not yet fully understood, but excitatory and inhibitory processes are most probably involved. Several animal and human studies have shown that hippocampal dysfunction might contribute to the aberrant dopamine release in schizophrenia making the hippocampus a valid target for stimulation. 
Mikell and colleagues discuss that the inhibition or stabilisation of neural activity in the hippocampus or nucleus accumbens might reduce positive symptoms of schizophrenia.(10) However, such optimism should be treated with caution because there are no long-term results on the efficacy and tolerability of stimulating electrodes in the brain. Also, the fundamental ethical concerns inherent in DBS are more pronounced in patients suffering from schizophrenia because they might be less able to take part in the decision-making processes compared with patients suffering from other conditions, such as major depression. Until there is more knowledge and a better understanding of the pathophysiological and neurobiological mechanisms of DBS and effects beyond the improvement of positive symptoms, DBS should not be considered an appropriate treatment approach in schizophrenia patients.(11)
Developments in psychotherapy and rehabilitation strategies
In the past few years, interest has grown in psychotherapeutic approaches to the treatment of schizophrenia, and, with increasing recognition of its value, the motivation to improve and expand psychotherapeutic strategies has gained momentum. Today, cognitive behaviour therapy (CBT) has the strongest evidence base with significant  reduction of positive and negative symptoms, and improvement in social functioning and mood, when compared with standard psychiatric practice or another intervention.(12) 
However, there is increasing evidence for the positive effects of the newly developed therapeutic interventions, such as metacognitive training (MCT), which builds on the promising results of CBT and incorporates elements of psychoeducation and cognitive remediation.(13) MCT can be carried out either in small groups or individually and is composed of eight different modules addressing cognitive errors and problem-solving biases, such as attributional biases, jumping to conclusions, deficits in theory of mind and bias against disconfirmatory evidence. Further novel approaches in psychotherapy include narrative therapy with the focus on normalising the psychotic experience and mindfulness therapy, which supports the patient in accepting the experiences of illness in a non-judgmental way. Work is underway to develop methods to reliably study and evaluate these new approaches.
Another important area in the field of psychotherapy and rehabilitation are programmes that improve and remediate cognitive impairments; psychopharmacological treatments have a limited effect in these areas. 
Different programmes exist, for example specific targeted cognitive training with the primary goal of increasing working memory capacity and improving cognitive control and response efficacy to salient targets; computer training in these areas leads to improvements in verbal learning, memory and control. Another approach integrates computer-based neurocognitive training and social-cognitive group sessions (cognitive enhancement therapy), which has been shown to produce strong and lasting improvements in cognition and functioning in schizophrenia patients. Comprehensive cognitive rehabilitation programmes are also associated with protective effects against grey matter loss, which underlines the positive effects on the brain of such therapeutic approaches.(14)
In the last decade, new non-dopaminergic drugs have been developed that indirectly modulate the dopamine system and possibly mark the next generation of antipsychotic drugs thus reflecting our improved understanding of the disease. Further clinical studies have to show the applicability, effectiveness and tolerability of these novel drugs. In addition to the new drugs, neuromodulational and psychotherapeutic treatments will hopefully significantly improve the future treatment of schizophrenia.
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