A new nosology of psychosis and the pharmacological basis of affective and negative symptom dimensions in schizophrenia

Abstract

Although first rank symptoms focus on positive symptoms of psychosis they are shared by a number of psychiatric conditions. The difficulty in differentiating bipolar disorder from schizophrenia with affective features has led to a third category of patients often loosely labeled as schizoaffective. Research in schizophrenia has attempted to render the presence or absence of negative symptoms and their relation to etiology and prognosis more explicit. A dichotomous population is a recurring theme in experimental paradigms. Thus, schizophrenia is defined as process or reactive, deficit or non-deficit and by the presence or absence of affective symptoms. Laboratory tests confirm the clinical impression showing conflicting responses to dexamethasone suppression and clearly defined differences in autonomic responsiveness, but their patho-physiological significance eludes mainstream theory. Added to this is the difficulty in agreeing to what exactly constitutes useful clinical features differentiating, for example, negative symptoms of a true deficit syndrome from features of depression. Two recent papers proposed that the general and specific cognitive features of schizophrenia and major depression result from a monoamine-cholinergic imbalance, the former due to a relative muscarinic receptor hypofunction and the latter, in contrast, to a muscarinic hypersensitivity exacerbated by monoamine depletion. Further development of these ideas will provide pharmacological principles for what is currently an incomplete and largely, descriptive nosology of psychosis. It will propose a dimensional view of affective and negative symptoms based on relative muscarinic integrity and is supported by several exciting intracellular signaling and gene expression studies. Bipolar disorder manifests both muscarinic and dopaminergic hypersensitivity. The greater the imbalance between these two receptor signaling systems, the more the clinical picture will resemble schizophrenia with bizarre, incongruent delusions and increasingly disorganized thought. The capacity for affective expression, by definition a non-deficit syndrome, will remain contingent on the degree of preservation of muscarinic signaling, which itself may be unstable and vary between trait and state examinations. At the extreme end of muscarinic impairment, a deficit schizophrenia subpopulation is proposed with a primary and fixed muscarinic receptor hypofunction.The genomic profile of bipolar disorder and schizophrenia overlap and both have a common dopaminergic intracellular signaling which is hypersensitive to various stressors. It is proposed that the concomitant muscarinic receptor upregulation differentiates the syndromes, being marked in bipolar disorder and rather less so in schizophrenia. From a behavioral point of view non-deficit syndromes and bipolar disorder appear most proximate and could be reclassified as a spectrum of affective psychosis or schizoaffective disorders. Because of a profound malfunction of the muscarinic receptor, the deficit subgroup cannot ex...

Aligning physiology with psychology: Translational neuroscience in neuropsychiatric drug discovery

“…This emphasis would provide an empirical basis for classification as well as aetiology. Importantly, the development of DSM-5 illustrates the move away from purely categorical through the recognition that psychiatric disorders represent a spectrum with dimensions of severity rather than distinct entities (Ghaemi et al, 2001;Lauritsen, 2013;Vakalopoulos, 2010).…”

The effect of deficient muscarinic signaling on commonly reported biochemical effects in schizophrenia and convergence with genetic susceptibility loci in explaining symptom dimensions of psychosis

“…A biological premise for implicit memory in affective disorders ( Vakalopoulos, 2007 ) was proposed to elucidate the signaling pathways involved in the emotional dysregulation of psychotic disorders ( Vakalopoulos, 2010 ). Convergent signaling of N -methyl- D -aspartate (NMDA), brain derived neurotrophic factor (BDNF), dopamine D3R (Gi) and muscarinic M1R (Gq/11) is involved in the learning and expression of emotional behavior.…”

“…Pathognomonic learning impairments have been proposed for schizophrenia and these should reflect signaling changes. It remains important to describe these correlations in higher-level psychological terms ( Vakalopoulos, 2010 ). An elegant study in a group of 15 patients with a DSM IV diagnosis of schizophrenia or schizoaffective disorder showed a profound deficit in LTP-like enhancement of motor evoked potential (MEP) amplitude during a paired associative stimulation paradigm ( Figure 1 ).…”

“…Several of the authors later propose an indirect mechanism for the pathophysiology of psychosis involving M4 midbrain autoreceptors, a loss which paradoxically increases cholinergic drive of dopaminergic nuclei and neurotransmitter levels ( Tzavara et al, 2004 ). A more direct effect M4 deficit on intracellular signaling and monoamine-muscarinic imbalance was proposed as causal in declarative memory deficits associated with schizophrenia ( Vakalopoulos, 2006 , 2010 ).…”

Attentional and emotional functioning in schizophrenia patients treated with conventional and atypical antipsychotic drugs

“…Some clinical studies suggest that atypical antipsychotic drugs bring about improvement in cognitive symptoms, and that such improvement appears to be correlated with improvement of negative symptoms. This cognitive enhancement may be mediated by increases in dopamine and acetylcholine in prefrontal dorsolateral regions, and in those parts of the hippocampus associated with the acquisition and consolidation of new information [2–4]. …”