The Case for Early Treatment of Schizophrenia
Dr. Jeffrey A. Lieberman, MD, presenting at the American Psychiatric Association 2007 Annual Meeting discussed the role of intervention during the early phase of schizophrenia (called the "prodrome") that may be possible in the cases in which schizophrenia develops when the person is 15-25 years of age (the most common period for schizophrenia to develop, though women tend to get schizophrenia slightly later than men). Dr. Lieberman describes schizophrenia as a neurodegenerative process that is not as complete as in Alzheimer's disease but in which patients can never-the-less live with chronic disability from negative and cognitive symptoms.
Schizophrenia is believed (by Dr. Lieberman) to be the result of genes causing abnormal neural circuits to be formed in the brain. This lays the groundwork for the "genetic susceptibility" observed upon which the environmental factors then act to further increase risk or precipitate the full-blown illness. The number of environmental factors that can act upon this genetic susceptibility are numerous, and include pregnancy factors such as nutrition, birth factors such as oxygen deprivation or premature birth, and early life events such as exposure to toxins, infections, social stress, trauma, or illicit drugs.
Although it is the eventual psychosis that gets the attention, the initial symptoms of the illness may include subtle changes in behavior and ability to regulate mood.
According to Dr. Lieberman, schizophrenia comprises 3 stages: prodromal, active deterioration, and residual.
Of great concern is the possibility that repeated episodes of psychosis may cause further deterioration of the brain (as evidenced using neuroimaging techniques) with worsening treatment response. But even with treatment, some brain loss is still seen.
It is therefore important not only to treat as early as possible, prevent recurrent psychosis, but also to find treatments and therapies that will stop the deterioration of the brain and help in the regrowth of the brain cells (neurons), called neurogenesis.
Early research is showing that some atypical antipsychotics may have an advantage over older antipsychotics by promoting some degree of neurogenesis in at least some portions of the brain. Other psychotherapies and computer-based therapies are also showing value in this area. There is on-going research on these topics.
Read the article: Medscape Perspectives on the 2007 Annual Sessions of the American Psychiatric Association: The Case for Early Psychosis Intervention (Free registration required)
Related Reading:
Preventing Schizophrenia
Global List of Early Psychosis Treatment Centers
Early Treatment with Antidepressants May Prevent Schizophrenia
"The Early Course of Schizophrenia": Book Review
Barriers Facing Young People Seeking Help for First Episode Psychosis
San Francisco - New Early Schizophrenia Treatment Program
Neurodevelopment and high risk of psychosis
Posted by Jeanie Wolfson at May 31, 2007 06:45 AM
More Information on
Early Schizophrenia Treatment
Hyperfunction (Alzheimer’s disease and Parkinson disease) and hypofunction (schizophrenia) of glutamatergic neurons
Neurodegeneration is a multifaceted process involving, among others, the unbalance of the glutamatergic system. Prolonged exposure of neurons to moderate-to-high concentrations of L-glutamate irreversibly culminates in neuronal damage. It is generally accepted that the influx of Ca2+ as a result of excessive activation of the NMDA receptor underlies the toxic actions of glutamate in many systems. During periods of ischemia and in many neurodegenerative diseases, excessive stimulation of glutamate receptors is thought to occur. These neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease…, are caused by different mechanisms but may share a final common pathway to neuronal injury due to the overstimulation of glutamate receptors, especially of the NMDA subtype.
And what is known about overstimulation of NMDA receptor in other neurodegenerative „mad cow disease” (BSE)? There we described an alternative „ammonia- magnesium BSE theory“ (Fig.1), see journal „Feed-Mix“(No 2, 2002) (http://www.agriworld.nl/feedmix/headlines.asp?issue=3);
On the other hand a hypofunction of glutamatergic neurons has been hypothesized to caused schizophrenia. For example, see conclusions from the symposium entitled, "Not Just Dopamine Any More: Emerging Glutamatergic Therapies for Schizophrenia," (Toronto, 2006) http://www.medscape.com/viewarticle/537385
Calcium deficiency may be a predisposing or causative factor in schizophrenia ?
Recently, evidence is accumulating that the exclusive dopamine hypothesis of schizophrenia has to be abandoned because significant additional evidence has accumulated supporting a role for NMDA hypofunction in the pathophysiology of schizophrenia. Clinical challenge studies with NMDA antagonist have confirmed the close resemblance between NMDA antagonist-induced symptoms and neurocognitive deficits and those observed in schizophrenia, and suggest that NMDA dysfunction may lead to secondary dopaminergic dysregulation in striatal and prefrontal brain regions. NMDA receptors on the GABAergic interneurons of brain areas affected by schizophrenia are „NMDA hypofunctional“. Activation of the NMDA receptor channel can occur only if there is simultaneous glutamate and glycine binding and partial depolarisation of the membrane potential.
However, treatment studies with NMDA modulators, such as glycine, D-serine, and glycine transport inhibitors (GTIs), have yielded encouraging findings, although results remain controversial. Why? Because- perhaps, NMDA receptors might have a lower affinity for glycine, explaining why administration of exogenous glycine-agonists results in a favorable clinical response in schizophrenia. Additionally, one could imagine that these receptors might be less sensitive to glutamate, and, perhaps, more sensitive to Mg2+ block . So, NMDA receptors may differ in their sensitivity to voltage-dependent Mg2+ block, agonists, and antagonists as a function of their subunit composition.
Thus, functional diversity of NMDA receptors may be expected from the assembly of different subunit combinations, and there is very important „Ca2+-dependent manner” which permits activation of NMDA receptors … So, dietary calcium deficiency can be important about „NMDA hypofunction“ in schizophrenia… Calcium in cells is tightly regulated and mostly unrelated to necessary dietary calcium. However, a low content of calcium in the ration decreases the magnesium requirements of the animal. The lower the calcium level in the animal- human ration (and in the tissue cells); the more marked is „NMDA receptors blocking effect of Mg2+ “; both intracellularly and extracellularly.
Maintenance of the body calcium stores depends mainly on dietary Ca intake, and on absorption of Ca from the gastrointestinal (GI) tract. For example, the majority of Americans do not get enough calcium in their diet- nearly 75 percent of women and 50 percent of men according to the United States Department of Agriculture (USDA). And only 14 percent of teen girls and 35 percent of teen boys are meeting the recommended dietary allowance. This deficit is a crippling statistic considering how critical calcium is to the body's infrastructure. But now with the innovation of a double-calcium fluid milk, every cookie dunk, spoonful of cereal and breakfast smoothie can provide twice the nutrient that can help reduce the risk of osteoporosis, keep teeth strong, battle high blood pressure and may even aid weight loss as part of a reduced calorie diet (Medical News Today, 2004).
In addition, diets moderate in protein (in the approximate range of 1.0 to 1.5 g protein/kg) are associated with normal calcium metabolism At low protein intakes, intestinal calcium absorption is reduced, resulting in increases in serum PTH; as induced secondary hyperparathyroidism. Hypoproteinemia is associated with a decrease in total calcium, hypoproteinemia can reduce the protein-bound fraction of plasma calcium. Calcium is an important component of a healthy diet. Calcium supplements are used to prevent and to treat calcium deficiencies. There are conflicting recommendations about when to take calcium supplements. However, most experts agree that no more than 500 mg should be taken at a time because the percent of calcium absorbed decreases as the amount of calcium in the supplement increases. It is recommended to spread doses throughout the day, with the last dose near bedtime. Recommended daily calcium intake varies from 1000 to 1500 mg, depending upon the stage of life.
Calcium plays a vital role in the physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. The amount of total calcium varies with the level of serum albumin, a protein to which calcium is bound. The biologic effect of calcium is determined by the amount of ionized calcium, rather than the total calcium. The skeleton acts as a major mineral storage site for the element and releases Ca2+ ions into the bloodstream under controlled conditions. In mammals, levels of intracellular calcium are regulated by transport proteins that remove it from the cell. Ca2+ entering the cell plasma causes the specific action of the cell, whatever this action is: secretory cells release vesicles with their secretion, muscle cells contract, synapses release synaptic vesicles and go into processes of synaptic plasticity, etc. Ca2+ ions are one of the most widespread second messengers used in signal transduction. They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels (such as Ca- binding proteins), or from some internal calcium storages. So, calcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. However, derangements of this mechanism can lead to “calcium- deficiency”, which can have important consequences in health of “schizophrenic individuals”. This concept is based on the demonstration that „NMDA receptor hypofunction“ can be based on calcium-deficiency, potentiated by nutritional hypoproteinemia (see Fig.2), see website www.bse-expert.cz , chapter “Hyperfunction (Alzheimer’s disease and Parkinson disease) and hypofunction (schizophrenia) of glutamatergic neurons”.
What is necessary about the prevention of „NMDAR hypofunction“ ?
Activation of the NMDA receptor (NMDAR) channel can occur only if there is simultaneous glutamate and glycine binding and partial depolarisation of the membrane potential according to following steps (see NMDA receptors activation);
1. Sustained activation of AMPA receptors (AMPAR) by, for instance, a train of impulses arriving at a pre-synaptic terminal, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDAR activation
2. Ambient glutamate in the nerve synaptic cleft activates Ca2+-permeable AMPAR on the postsynaptic neurons. This allows an influx of Ca2+ that causes a gradual increase in intracellular calcium concentrations [Ca2+]i
3. The recruitment of NMDAR during high presynaptic glutamatergic activity results in the permanent increase in synaptic efficacy known as long-term potentiation (LTP). Influx of Ca2+ through the NMDAR during LTP causes the recruitment of AMPAR from intracellular stores to the synapse.
4. Activation of AMPA presynaptic receptors at physiological pH (pH 7.4) elicits the release of the [3H]transmitters in an external Ca2+-dependent manner ( so, AMPAR activation induces a Ca2+-dependent release of noradrenaline, dopamine…)
5. Activation of AMPAR permits activation of NMDAR in the presence of physiological concentrations of Mg2+ (nerve endings are endowed with presynaptic receptors of the AMPA type, whose activation induces a Ca2+-dependent, exocytotic-like release of neurotransmitters).
6. So, NMDAR activation begins when sustained activation of AMPAR, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDAR activation.
7. NMDAR activation occurs only when the neuron is partially depolarized (more positively charged), following activation of AMPAR
8. NMDAR channel is blocked by Mg2+, which is removed upon depolarization. So when glutamate and glycine bind and the cell is depolarized to remove Mg2+ block, the NMDAR channel opens with consequent influx of Ca2+ and Na+ into the cell
9. On the other hand; at hyperpolarized membrane potentials more negative than about −70 mV, the concentration of Mg2+ in the extracellular fluid of the brain is sufficient to virtually abolish ion flux through NMDAR channels even in the presence of the coagonists glutamate and glycine
10. Astrocytes (glial cells) are important in controlling glutamate homeostasis. [Ca2+]i elevations in astrocytes stimulate the release of glutamate, which acting on presynaptic or postsynaptic receptors, modulates synaptic transmission and neuronal excitability. So, astrocytic glutamate release is Ca2+ -dependent and can be triggered by any ligand that stimulates an increase in [Ca2+]i
11. In addition, about simultaneous glutamate and glycine binding; D-serine, SR enzyme and transporter GLYT-1; are present mainly in glial cells
12. D-Serine is the endogenous ligand for the glycine site of the glutamate NMDAR, which coactivates postsynaptic NMDA receptors together with glutamate
13. The availability of D-serine depends upon the activities of serine racemase (SR) enzyme because SR directly converts L-serine to D-serine. D-serine and SR are concentrated in astrocytes adjacent to NMDA receptors, but less common or nonexistent in other neural tissues
14. Divalent cations such as calcium or manganese are necessary for complete SR enzyme activity. It was suggested that there might be a glutamatergic-mediated regulation of SR activity by intracellular Ca2+ concentration.
15. Glycine acts as an obligatory coagonist of glutamate at NMDAR. This role depends on extracellular glycine levels, regulated by Na+/Cl−-dependent transporter GLYT-1, present mainly in glial cells. High affinity transport by GLYT-1 is regulated by [Ca2+]i from intracellular stores.
Posted by: Josef Hlasny at June 1, 2007 02:18 AM
"...intervention during the early phase of schizophrenia (called the "prodrome") that may be possible in the cases in which schizophrenia develops when the person is 15-25 years of age (the most common period for schizophrenia to develop)."
Most people will see this as just nit-picking, but given that the age of onset is typically higher in women than the age range mentioned, I wonder how much of the rest of this article is based on research presuming that the male is the default measure of schizophrenia which will fallaciously, dangerously, and unjustly be misapplied to every other group, including women.
Even in this day and age, almost every medical and safety standard (e.g., car crash trials) consider men's health the default, and it's sad to see this study may be no different.
Posted by: K.A. at June 2, 2007 03:39 PM
Hyperfunction (Alzheimer’s disease and Parkinson disease) and hypofunction (schizophrenia) of glutamatergic neurons
Neurodegeneration is a multifaceted process involving, among others, the unbalance of the glutamatergic system. Prolonged exposure of neurons to moderate-to-high concentrations of L-glutamate irreversibly culminates in neuronal damage. It is generally accepted that the influx of Ca2+ as a result of excessive activation of the NMDA receptor underlies the toxic actions of glutamate in many systems. During periods of ischemia and in many neurodegenerative diseases, excessive stimulation of glutamate receptors is thought to occur. These neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease…, are caused by different mechanisms but may share a final common pathway to neuronal injury due to the overstimulation of glutamate receptors, especially of the NMDA subtype.
And what is known about overstimulation of NMDA receptor in other neurodegenerative „mad cow disease” (BSE)? There we described an alternative „ammonia- magnesium BSE theory“ (Fig.1), see journal „Feed-Mix“(No 2, 2002) (http://www.agriworld.nl/feedmix/headlines.asp?issue=3);
On the other hand a hypofunction of glutamatergic neurons has been hypothesized to caused schizophrenia. For example, see conclusions from the symposium entitled, "Not Just Dopamine Any More: Emerging Glutamatergic Therapies for Schizophrenia," (Toronto, 2006) http://www.medscape.com/viewarticle/537385
Calcium deficiency may be a predisposing or causative factor in schizophrenia ?
Recently, evidence is accumulating that the exclusive dopamine hypothesis of schizophrenia has to be abandoned because significant additional evidence has accumulated supporting a role for NMDA hypofunction in the pathophysiology of schizophrenia. Clinical challenge studies with NMDA antagonist have confirmed the close resemblance between NMDA antagonist-induced symptoms and neurocognitive deficits and those observed in schizophrenia, and suggest that NMDA dysfunction may lead to secondary dopaminergic dysregulation in striatal and prefrontal brain regions. NMDA receptors on the GABAergic interneurons of brain areas affected by schizophrenia are „NMDA hypofunctional“. Activation of the NMDA receptor channel can occur only if there is simultaneous glutamate and glycine binding and partial depolarisation of the membrane potential.
However, treatment studies with NMDA modulators, such as glycine, D-serine, and glycine transport inhibitors (GTIs), have yielded encouraging findings, although results remain controversial. Why? Because- perhaps, NMDA receptors might have a lower affinity for glycine, explaining why administration of exogenous glycine-agonists results in a favorable clinical response in schizophrenia. Additionally, one could imagine that these receptors might be less sensitive to glutamate, and, perhaps, more sensitive to Mg2+ block . So, NMDA receptors may differ in their sensitivity to voltage-dependent Mg2+ block, agonists, and antagonists as a function of their subunit composition.
Thus, functional diversity of NMDA receptors may be expected from the assembly of different subunit combinations, and there is very important „Ca2+-dependent manner” which permits activation of NMDA receptors … So, dietary calcium deficiency can be important about „NMDA hypofunction“ in schizophrenia… Calcium in cells is tightly regulated and mostly unrelated to necessary dietary calcium. However, a low content of calcium in the ration decreases the magnesium requirements of the animal. The lower the calcium level in the animal- human ration (and in the tissue cells); the more marked is „NMDA receptors blocking effect of Mg2+ “; both intracellularly and extracellularly.
Maintenance of the body calcium stores depends mainly on dietary Ca intake, and on absorption of Ca from the gastrointestinal (GI) tract. For example, the majority of Americans do not get enough calcium in their diet- nearly 75 percent of women and 50 percent of men according to the United States Department of Agriculture (USDA). And only 14 percent of teen girls and 35 percent of teen boys are meeting the recommended dietary allowance. This deficit is a crippling statistic considering how critical calcium is to the body's infrastructure. But now with the innovation of a double-calcium fluid milk, every cookie dunk, spoonful of cereal and breakfast smoothie can provide twice the nutrient that can help reduce the risk of osteoporosis, keep teeth strong, battle high blood pressure and may even aid weight loss as part of a reduced calorie diet (Medical News Today, 2004).
In addition, diets moderate in protein (in the approximate range of 1.0 to 1.5 g protein/kg) are associated with normal calcium metabolism At low protein intakes, intestinal calcium absorption is reduced, resulting in increases in serum PTH; as induced secondary hyperparathyroidism. Hypoproteinemia is associated with a decrease in total calcium, hypoproteinemia can reduce the protein-bound fraction of plasma calcium. Calcium is an important component of a healthy diet. Calcium supplements are used to prevent and to treat calcium deficiencies. There are conflicting recommendations about when to take calcium supplements. However, most experts agree that no more than 500 mg should be taken at a time because the percent of calcium absorbed decreases as the amount of calcium in the supplement increases. It is recommended to spread doses throughout the day, with the last dose near bedtime. Recommended daily calcium intake varies from 1000 to 1500 mg, depending upon the stage of life.
Calcium plays a vital role in the physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. The amount of total calcium varies with the level of serum albumin, a protein to which calcium is bound. The biologic effect of calcium is determined by the amount of ionized calcium, rather than the total calcium. The skeleton acts as a major mineral storage site for the element and releases Ca2+ ions into the bloodstream under controlled conditions. In mammals, levels of intracellular calcium are regulated by transport proteins that remove it from the cell. Ca2+ entering the cell plasma causes the specific action of the cell, whatever this action is: secretory cells release vesicles with their secretion, muscle cells contract, synapses release synaptic vesicles and go into processes of synaptic plasticity, etc. Ca2+ ions are one of the most widespread second messengers used in signal transduction. They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels (such as Ca- binding proteins), or from some internal calcium storages. So, calcium metabolism or calcium homeostasis is the mechanism by which the body maintains adequate calcium levels. However, derangements of this mechanism can lead to “calcium- deficiency”, which can have important consequences in health of “schizophrenic individuals”. This concept is based on the demonstration that „NMDA receptor hypofunction“ can be based on calcium-deficiency, potentiated by nutritional hypoproteinemia (see Fig.2), see website www.bse-expert.cz , chapter “Hyperfunction (Alzheimer’s disease and Parkinson disease) and hypofunction (schizophrenia) of glutamatergic neurons”.
What is necessary about the prevention of „NMDAR hypofunction“ ?
Activation of the NMDA receptor (NMDAR) channel can occur only if there is simultaneous glutamate and glycine binding and partial depolarisation of the membrane potential according to following steps (see NMDA receptors activation);
1. Sustained activation of AMPA receptors (AMPAR) by, for instance, a train of impulses arriving at a pre-synaptic terminal, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDAR activation
2. Ambient glutamate in the nerve synaptic cleft activates Ca2+-permeable AMPAR on the postsynaptic neurons. This allows an influx of Ca2+ that causes a gradual increase in intracellular calcium concentrations [Ca2+]i
3. The recruitment of NMDAR during high presynaptic glutamatergic activity results in the permanent increase in synaptic efficacy known as long-term potentiation (LTP). Influx of Ca2+ through the NMDAR during LTP causes the recruitment of AMPAR from intracellular stores to the synapse.
4. Activation of AMPA presynaptic receptors at physiological pH (pH 7.4) elicits the release of the [3H]transmitters in an external Ca2+-dependent manner ( so, AMPAR activation induces a Ca2+-dependent release of noradrenaline, dopamine…)
5. Activation of AMPAR permits activation of NMDAR in the presence of physiological concentrations of Mg2+ (nerve endings are endowed with presynaptic receptors of the AMPA type, whose activation induces a Ca2+-dependent, exocytotic-like release of neurotransmitters).
6. So, NMDAR activation begins when sustained activation of AMPAR, depolarises the post-synaptic cell, releasing the channel inhibition and thus allowing NMDAR activation.
7. NMDAR activation occurs only when the neuron is partially depolarized (more positively charged), following activation of AMPAR
8. NMDAR channel is blocked by Mg2+, which is removed upon depolarization. So when glutamate and glycine bind and the cell is depolarized to remove Mg2+ block, the NMDAR channel opens with consequent influx of Ca2+ and Na+ into the cell
9. On the other hand; at hyperpolarized membrane potentials more negative than about −70 mV, the concentration of Mg2+ in the extracellular fluid of the brain is sufficient to virtually abolish ion flux through NMDAR channels even in the presence of the coagonists glutamate and glycine
10. Astrocytes (glial cells) are important in controlling glutamate homeostasis. [Ca2+]i elevations in astrocytes stimulate the release of glutamate, which acting on presynaptic or postsynaptic receptors, modulates synaptic transmission and neuronal excitability. So, astrocytic glutamate release is Ca2+ -dependent and can be triggered by any ligand that stimulates an increase in [Ca2+]i
11. In addition, about simultaneous glutamate and glycine binding; D-serine, SR enzyme and transporter GLYT-1; are present mainly in glial cells
12. D-Serine is the endogenous ligand for the glycine site of the glutamate NMDAR, which coactivates postsynaptic NMDA receptors together with glutamate
13. The availability of D-serine depends upon the activities of serine racemase (SR) enzyme because SR directly converts L-serine to D-serine. D-serine and SR are concentrated in astrocytes adjacent to NMDA receptors, but less common or nonexistent in other neural tissues
14. Divalent cations such as calcium or manganese are necessary for complete SR enzyme activity. It was suggested that there might be a glutamatergic-mediated regulation of SR activity by intracellular Ca2+ concentration.
15. Glycine acts as an obligatory coagonist of glutamate at NMDAR. This role depends on extracellular glycine levels, regulated by Na+/Cl−-dependent transporter GLYT-1, present mainly in glial cells. High affinity transport by GLYT-1 is regulated by [Ca2+]i from intracellular stores.
Posted by: Josef Hlasny at June 1, 2007 02:18 AM
"...intervention during the early phase of schizophrenia (called the "prodrome") that may be possible in the cases in which schizophrenia develops when the person is 15-25 years of age (the most common period for schizophrenia to develop)."
Most people will see this as just nit-picking, but given that the age of onset is typically higher in women than the age range mentioned, I wonder how much of the rest of this article is based on research presuming that the male is the default measure of schizophrenia which will fallaciously, dangerously, and unjustly be misapplied to every other group, including women.
Even in this day and age, almost every medical and safety standard (e.g., car crash trials) consider men's health the default, and it's sad to see this study may be no different.
Posted by: K.A. at June 2, 2007 03:39 PM