Dr. Grossi's Blog
Why I am asked a surprisingly large number of questions about schizophrenia in light of the fact that I have no such patients in my practice remains almost as much a mystery as the disorder itself. I assume that this represents a curiosity about a common psychiatric topic in the lay press. This manifest interest has led me to devote this blog to informing my readers and patients so that I do not have to repeat myself and to guarantee a more complete presentation of the current thinking and state of knowledge about this devastating and debilitating disorder that affect about 1% of the worldwide population than would be the case in an off-handed discussion. I plan to discuss the phenomenology, signaling pathways, and genetics but not the treatment.
It typically appears in late adolescent years or sometimes in early adulthood and produces profound disability. It is usually described as having positive and negative characteristics. The positive ones include hallucinations (usually auditory), delusions, disorganized or loose thought and speech and/or behavior and sometimes intense paranoia (suspiciousness, mistrustfulness). The negative symptoms include social withdrawal, poor social relatedness, enormously reduced affective expressions (flat affect), lack of motivation, as well as cognitive deficits that include reduced working memory, reduced and defective attention, slowed mental processing speed, and impaired executive function. They often have mood symptoms and a high incidence of substance abuse. The group shows a suicide rate of approximately 10% (behind bipolar I who manifest a 15% lifetime suicide rate) and approximately 85% smoke cigarettes which is over three time the US population average.
Psychiatric researchers who focus on this disorder have come to believe that it is a neurodevelopmental disorder with genetic risk and very poorly defined but present neuropathology. The current thinking is that there is an endophenotype (think colonic polyps that eventually become cancerous) present from very early years but that do not present until adolescence or early adulthood. There are no practical diagnostic tests at this time but there are a few hard findings in the group which include reduced volume of the temporal lobe, enlarged ventricles in the brain, and increased dopamine in the striatum (includes the caudate and putamen).
Like all other psychiatric diseases that I can think of, Schizophrenia is a multi-factorial disorder with inputs from susceptibility genes (many), environmental factors, and epigenetic contributions (this is really a miscellaneous category because it really means any effect that influences whether a gene is turned on or off and/or when it is turned on or off --this could be by methylation or some other mechanisms heretofore unknown) or even stochastic. Numerous family, twin, and population studies support genetic factors at work. As indicated above, about 1% of the population suffers from this disorder but about 50% of identical twins are concordant for the disease, i.e., a 1% prevalence versus a 50% prevalence. Genes and the environment do interact as manifested by an increased risk with prenatal malnutrition and infections as well as obstetrical complications and perinatal hypoxia. Other factors that increase risk are urban living and stress during the adolescent years and cannabis use in early adolescence. The brain is plastic during the adolescent years.
From a genetic-susceptibility-underlying-disease standpoint, the penetrance and prevalence of risk alleles are the key variables. There are two prevailing hypotheses. The first is the common disease-common allele hypothesis and the second is the common disease-rare allele hypothesis. The first states that common small effect alleles act together to cause disease. The second states that rare but highly penetrant alleles cause disease. These are not boolean but rather should be seen as acting together in the final common pathway. The allele findings so far are nonspecific and thus are shared by syndromes such as schizophrenia, bipolar disorder, unipolar depression, and autism.
So what are some of these genetic abnormalities and with what are they associated? The 22q11DS congenital malformation syndrome is caused by microdeletions and approximately 30% of children with this develop schizophrenia and that accounts for about 2% of of non-familial schizophrenia. Proline dehydrogenase (PRODH) is coded for at the 22q11.2 locus. In knockout mice with the defect there is decreased density of glutaminergic synapses and impaired connectivity between hippocampus and the prefrontal cortex. ZDHHC8 is another implicated gene at 22q11 locus encodes a palmitoylation transferase. In mouse knockout models neurons in the hippocampus are affected and there is cognitive and behavioral deficits. Another implicated gene is COMT which encodes for catechol-O-methyltransferase and is also located in the 22q11 locus. This is a complex gene with certain alleles sffecting stability and others levels of expression. It is involved in catecholamine metabolism. New research shows that COMT and PRODH interact in complex ways. Several other implicated genes are NRG1,. DISC1, AKT1, and PI3K and its promoter region PI3KC3. This is obviously a daunting area with definitive solutions far off but progress is being made very, very slowly.
Signaling pathways in the brain in schizophrenia are equally challenging to understand and is substantially incomplete. The NMDA antagonists ketamine and PCP aggravate the symptoms in people who have schizophrenia by glutaminergic interference. Another glutamatergic receptor mGluR when under the influence of an agonist can reverse some of the effects of PCP. Abnormalities in GABA transmission have been identified in schizophrenics and are associated with poor cognitive functioning as well as working memory. Cholinergic signaling has been implicated in the processes of attention, working memory, and motivation. The high rate of smoking as mentioned above has been interpreted as an attempt at self-medication and specifically to address cognitive and sensory filtering deficits. Finally, fewer M1 muscarinic receptors are found in the cortical areas of schizophrenic patients which is thought to adversely impact working memory-related performance.
Among the variety of problems that present in the office, this is the most perplexing and difficult to treat adequately. I hope the reader gets a sense of the complexity of the problem from the above discussion.
Memory is divided into two major aspects --declarative and procedural. The first is declarative memory which is divided into semantic memory and episodic memory, which is the memory for autobiographical events including times, places, events, associated emotions and contextual knowledge. The counterpart to declarative memory is procedural or implicit memory. Implicit memory is memory in which prior experience aids in the performance of task without consciousness awareness of previous experience. Procedural memory, a type of implicit memory, is the memory of how to do things such as tying our shoes or ties or driving a car. There is no conscious control and it is long-term memory. Evidence for implicit memory comes from priming experiments and amnestic patients who are unimpaired in performing such tasks. There are two forms of amnesia: anterograde amnesia in which a person is unable to memorize new events or data and retrograde in which an individual cannot consciously recall pre-existing memories.
The hippocampus is a paired structure, mirror image on left and right, embedded deep in the medial temporal lobes and a core part of the limbic system. The textbooks tell us that it encodes new memories as memory traces that are eventually consolidated in the cortex for long-term storage. Once the memories are in the cortex, the hippocampus is no longer needed to store or retrieve the memories. Yet a new study raises some questions about this standard position.
Eleanor A. Maguire and colleagues at the University College of London published in the Proceedings of the National Academy Science USA in 2007 a study of 5 amnestic patients with primary damage to the hippocampus bilaterally, compared to 10 controls who were matched for age, education, and IQ. They presented short verbal cues and asked the individuals to elaborate a future experience based on those cues. The cues were beach, pub, port, museum, forest, and castle. They found that those with amnestic damage were markedly impaired in producing new imagined experiences. The productions were characterized by fragmentation and lacking in a holistic representation of the setting. The examples they gave are striking in showing the lack of spatial coherence. It would thus appear that hippocampal lesions withdraw the spatial context that allows for disparate elements of a new experience to be ordered. Within the standard understanding, the hippocampus is a time-limited contributor in episodic memory as the neocortex assumes long-term storage including generalized representations for spatial contextual (e.g. port) and nonspatial (e.g. object)memories. In this model, hippocampal time-limited memories should not interfere with imaginative productions because the neocortical areas should actively support such imaginative productions yet it seems to interfere. Therefore there is question about the standard explanation.
De Drue et al. published an article entitled "The Neuropeptide Oxytocin Regulates Parochial Altruism in Intergroup Conflicts Among Humans" in the 11 June 2010 issue of Science. Parochial altruism is defined as self-sacrifice to benefit our own group ("in-group love") and to hurt or sabotage out-groups ("out-group aggression"). In-group love supports the power of the in-group and is an indirect way of competing with the out-group. Out-group aggression is a way of reducing the our-group's power and so an indirect way of supporting the in-group. This is an important explanation for human social evolution and the authors explore whether oxytocin is a part of the biological basis. Oxytocin, a nonapeptide made by the magnocellular neurons and released from the posterior pituitary, acts as a neurotransmitter and hormone, and influences the amygdala, hippocampus, brainstem and the autonomic nervous system through its influence on the spinal cord. The authors quote prior work that demonstrated that affiliating with close kin associates with increases in blood plasma oxytocin. Greater empathy, generosity and other-regarding preferences associate with increased oxytocin receptors (OXTR). They also note that oxytocin administered by nasal spray promotes trust and cooperation and reduces the tendency to take advantage of others.
Three experiments were designed to evaluate the in-group-out-group issues. All were placebo-controlled, double-blinded and involved male participants receiving nasal spray oxytocin or placebo. After thirty minutes, the participants were assigned to two three-person groups. The assigned group was the in-group and the other the out-group. They were introduced to prisoners dilemma game in which they made confidential decisions that had consequences for the fellow in-group and the our-group.
Analysis of the experiments goes beyond what I will discuss here due to time and complexity factors, however, what they suggest follows. It has been shown that oxytocin promotes social bonding in humans and animals. In this study, male participants made three confidential decisions between cooperation and noncooperation. The researchers postulated that since noncooperation with the out-group promotes in-group love they would expect it to be stronger under the influence of oxytocin. They also expected protectionism to be higher when out-group fear was high. What they found was that noncooperation was higher in those given oxytocin compared to placebo when out-group fear was high rather than low. They also showed that in-group protectionism and trust correlated with participant noncooperation toward the out-group. The authors state "these findings reflect a 'tend and defend' pattern in which oxytocin stimulates humans to aggress against out-group threat in order to protect their in-group."
So this work is another in a string of findings that link oxytocin to bonding pathways found in humans, voles, and zebra finches. It also illuminates a rational basis for considering altruism and aggression as close cousins. Finally, this study encompassed only half of humanity - males. How big a role this plays in our integration into groups and their success remains a question.