Neurotransmitter functions in depression

The understanding and management of depression has now progressed beyond the limitations imposed by clinical examination. Biochemical and pharmacological studies based on the biogenic amine hypothesis have investigated neurotransmitter mechanisms to varying degrees.

1. Subgroups of depressions may be identified and treated based on MHPG execution.

2. HVA correlates more with activity than with mood.

3. CSF-5HIAA may be helpful in categorising some depressions.

4. Acetylcholine has some effect on mood most probably through indirect action on other neurotransmitters.

5. GABA is still not adequately investigated.

6. Desensitization of presynaptic adrenergic autoreceptors may explain some of the mechanisms of antidepressant action of drugs.

7. Decreased post-synaptic adrenergic activity is a common effect of most antidepressants and of ECT.

Clinical effects of mianserin in endogenous depression and their relationship to drug plasma level

1. 1. This was a single-blind, open study undertaken to assess the antidepressant efficacy of mianserin, a new tetracyclic antidepressant in in-patients with major depression (DSM III).

2. 2. The relationship between steady state plasma levels and clinical response, and the predictability of steady-state mianserin plasma levels from a single point determination after an initial dose of the drug were also studied.

3. 3. There was remarkable clinical improvement as measured by the significant (P 0.001) reduction in mean HDRS scores after first week of active treatment which continued till day 28 when mean HDRS scores were reduced to about 50% of initial mean scores.

4. 4. There was a modest correlation (r = 0.623, n.s.) between the steady state levels of mianserin and the plasma concentration 12 hours after initial dose. No significant cardiovascular effect was noted throughout the course of treatment.

5. 5. Mianserin is a safe, efficacious antidepressant with minimal cardiovascular effects. Further clinical investigations of this new useful drug are recommended.

Activation of brain function by S-135, a benzodiazepine receptor inverse agonist

1. 1. S-135, 2-(5-methylthien-3-y1)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one, binds to benzodiazepine receptors with a high affinity and shows pharmacological actions opposite to those of conventional benzodiazepine drugs.

2. 2. S-135 induced no convulsion in mice by itself, but selectively potentiated the effect of subconvulsive dose of pentylenetetrazole.

3. 3. S-135 potentiated rat crossed extensor reflex and Ro 15-1788 completely antagonized this potentiation.

4. 4. S-135 antagonized pentobarbital-induced anesthesia, tetrabenazine-induced ptosis and reserpine-induced hypoactivity and shortened immobilization time in the despair test in mice, indicating that this compound possesses antidepressive properties.

5. 5. S-135 antagonized amnesia in mice and rats in passive avoidance tasks.

6. 6. Glucose utilization in brain areas relating to memory and arousal functions was enhanced following S-135 treatment.

7. 7. These results indicate that S-135 can be a useful drug for activating depressed brain function.

Dexamethasone effects on numbers of cells in lymphocyte subpopulations: Changes associated with major depression and DST nonsuppression

1. 1. The authors studied the effects of administration of 1 mg of dexamethasone on the number of cells in discrete subpopulations of lymphocytes in major depressed and psychiatric control patients with depressive symptoms.

2. 2. Dexamethasone significantly decreased the total lymphocyte count and numbers of T and helper T lymphocytes in control patients.

3. 3. In contrast, dexamethasone failed to significantly decrease the numbers of cells in any of the subpopulations of lymphocytes studied in major depressed patients.

4. 4. Among major depressed patients both DST suppressors and nonsuppressors were insensitive to the suppressive effects of dexamethasone on lymphocyte numbers.

5. 5. However, in DST nonsuppressors, but not in DST suppressors, dexamethasone administration significantly the number of cytotoxic/suppressor T lymphocytes and natural killer cells.

6. 6. The authors conclude that insensitivity to the suppressive effects of dexamethasone on lymphocyte numbers is specific to major depression and is not associated with DST status. However, DST nonsuppression is associated with a facilitating effect of dexamethasone on the number of cells in some subpopulations of lymphocytes.

Folic acid and psychopathology

1. 1. The incidence of folic acid deficiency is high in patients with various psychiatric disorders including depression, dementia and schizophrenia.

2. 2. In epileptics on anticonvulsants, folate deficiency often occurs because anticonvulsants inhibit folate absorption. In these patients folate deficiency is often associated with psychiatric symptoms.

3. 3. In medical patients psychiatric symptoms occur more frequently, and in psychiatric patients symptoms are more severe, in those with folate deficiency than in those with normal levels.

4. 4. Many open studies have demonstrated therapeutic effects of folate administration on psychiatric symptoms in folate deficient patients.

5. 5. Several placebo-controlled studies have not demonstrated therapeutic effects, possibly because the doses they used (15–20 mg/day) are known to be toxic and to cause mental symptoms.

6. 6. Two placebo-controlled studies have demonstrated beneficial effects of Folic acid administration, one in patients with a syndrome of psychiatric and neuropsychological changes associated with folate deficiency and the other in patients on long-term lithium therapy. In the latter study the dose was only 0.2 mg/day.

7. 7. Folic acid deficiency is known to lower brain S-adenosylmethionine and 5-hydroxy-tryptamine. S-Adenosylmethionine, which has antidepressant properties, raises brain 5-hydroxytryptamine. Thus, depression associated with folate deficiency is probably related to low brain 5HT.

8. 8. S-Adenosylmethionine is involved in many methylation reactions, including methylation of membrane phospholipids, which influences membrane properties. This may explain the wide variety of symptoms associated with folate deficiency.

9. 9. Because the costs and risks associated with low doses of folic acid (up to 0.5 mg/day) are small, folic acid should be given as an adjunct in the treatment of patients with unipolar or bipolar affective disorders and anorexia, epileptics on anticonvulsants, geriatric patients with mental symptoms and patients with gastrointestinal disorders who exhibit psychiatric symptoms.

10. 10. Although the majority of the patients listed above will probably not be helped by folic acid therapy, a significant minority are likely to have folate-responsive symptoms.

The effects of antidepressant drugs on adenylyl cyclase linked beta adrenergic binding sites on mouse astrocytes in primary cultures

1. 1) It has been widely reported that the chronic administration of antidepressant drugs induces a down regulation of beta receptors in the brains of experimental animals with a time course that parallels the therapeutic improvement seen in depressed patients given these drugs. It has been tacitly assumed that these beta receptors are located on neurons.

2. 2) All classes of antidepressant drugs tested, various monoamine uptake inhibitors, a monoamine oxidase inhibitor, or novel drugs lacking either of these actions, reduced the retention of dihydroalprenolol by intact astrocytes in primary cultures. The drug concentrations altering this retention by astrocytes (K_i) are in the same range as those reported by other investigators using homogenates of glioma cells or whole brain.

3. 3) The isoproterenol-induced stimulation of cyclic AMP formation by astrocytes in primary cultures is reduced acutely by the antidepressants amitriptyline, tranylcypromine and doxepin. Following washout of the antidepressant drug, isoproterenol stimulation of adenylyl cyclase is reduced in astrocytes exposed in culture to amitriptyline or tranylcypromine for 12–14 days or longer but is not altered in astrocytes exposed to the antidepressants for only 5 days.

4. 4) This indicates that the chronic exposure of astrocytes in culture to antidepressant drugs, down regulates astrocyte beta receptors with a time course that parallels the beta down regulation seen in vivo in animal brain homogenates and the therapeutic improvement seen in depressed patients. The possible functional aspects of drug astrocyte interactions must be considered in any hypothesis concerning drug-brain interactions.

The automated tail suspension test: A computerized device which differentiates psychotropic drugs

1. 1. Mice when suspended by the tail will alternate between active attempts to escape and immobility. Immobility like that measured in the behavioral despair test is reduced by a wide variety of antidepressant agents.

2. 2. The present paper describes a computerized version of this test (ITEMATIC-TST) which in addition to recording immobility measures the power of the movements.

3. 3. Various tricyclic (amitriptyline, desipramine, imipramine), MAOI (clorgyline, moclobemide, nialamide, pargyline, toloxatone) and atypical antidepressants (bupropion, citalopram, indalpine, miansenn, nomifensine, viloxazine) were tested and compared with psychostimulants (d-amphetamine, caffeine), neuroleptics (chlorpromazine, haloperidol, sulpiride), anxiolytics (clobazam, diazepam) and agents acting on the cholinergic system (atropine, oxotremorine).

4. 4. All antidrepressants decreased the duration of immobility and most increased the power of movements.

5. 5. The psychostimulants also decreased immobility but only amphetamine increased the power of movements.

6. 6. Neuroleptics increased immobility without affecting the power of movements, whereas anxiolytics increased immobility but decreased the power of movements.

7. 7. Atropine had a profile similar to antidepressants whereas oxotremorine tended to have opposite effects.

8. 8. The results suggest that the automated test system with its two parameters is not only sensitive to antidepressants but could also be useful for generating activity profiles for different kinds of psychotropic agent.

GABA and feeding: Reversal of overeating by central GABA-transaminase inhibition

1. 1. Past literature is reviewed briefly which suggests that variations in brain GABA metabolism may be involved in the control of food intake in rats.

2. 2. Recent experiments from the author's laboratory are summarized in which brain GABA has been elevated in adult female rats by intracisternal injection of the GABA-transaminase inhibitor ethanolamine-O-sulfate (EOS).

3. 3. Central EOS pretreatment produced dose-dependent anorexia in normal subjects and prevented acute overeating in response to systemic insulin (12 U/kg) or 2-deoxyglucose (750 mg/kg).

4. 4. Similar EOS pretreatment essentially reversed the chronic overeating induced by diet palatability bilateral medial hypothalamic lesions or genetic predisposition (in Zucker fatty rats).

5. 5. The ubiquity of these anorexic effects in the absence of clear motor debilitation suggests that Drugs Which elevate brain GABA deserve further investigation for their potential utility in the clinical treatment of overeating.

Strategies for studying the neurochemical substrates of drug reinforcement in rodents

1. 1. Results from three different experimental paradigms for studying drug reinforcement are reviewed.

2. 2. Rate-increasing effects of amphetamine on intracranial self-stimulation are abolished by lesions to ascending dopamine neurons.

3. 3. Rate-increasing effects of intracranial microinjection of opioids on self-stimulation are localized to the vicinity of dopamine cell bodies in the ventral tegmentum.

4. 4. Conditioned reinforcement produced with intracranial microinjection of opioids into the ventral tegmental area is blocked by the dopamine antagonist haloperidol and lesions to ascending dopamine pathways.

5. 5. Intravenous self-administration of cocaine is blocked by intracerebral microinjection of spiroperidol into the nucleus accumbens but not into the caudate nucleus.

6. 6. Ascending dopamine neurons appear to mediate some of the reinforcing properties of both psychomotor stimulants and opioids.

Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment

Wiesel, Frits-Axel: Regional glucose metabolism in schizophrenic patients before and during neuroleptic treatment. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 871–881.

1. 1. Determination of regional glucose metabolism has been considered to be a tool to elucidate the mechanisms of action of neuroleptics.

2. 2. D₂-dopamine antagonists seem to increase glucose consumption in dopamine innervated areas.

3. 3. Studies in humans do not give results in complete accordance with animal findings.

4. 4. In patients neuroleptic compounds and dopamin agonists probably increase and decrease striatal metabolism respectively.

5. 5. Changes in metabolism, especially in the right hemisphere may be coupled with improvement of the patients.

6. 6. Future research must be based on protocols specially designed for the study of drug effects.

Treatment of alcohol organic mental disorder with piracetam

1. 1. The paper presents an investigation of the efficiency of piracetam in alcohol organic mental disorder.

2. 2. A double blind placebo controlled study design was used to compare two dosages of the substance (2 × 3g versus 2 × 12g).

3. 3. The cognitive functions of the patients, especially short term memory and concentration, were assessed on the days 0, 7, 14, 28 and 42 using various psychological instruments.

4. 4. An analysis of 39 patients showed an improvement of cognitive functions in all three groups.

5. 5. Patients receiving drug treatment showed earlier responses than patients receiving placebo; differences between the three investigational groups were not statistically significant.

6. 6. The results achieved make the effect of piracetam appear somewhat questionable.

Assessment of agoraphobia and panic disorder

1. 1. Phobia and panic are defined by the measures used.

2. 2. Rating scales, diaries, global measures, physiological measures, behavioural assessment.

3. 3. Three fear systems: physiological, cognitive and behavioral

4. 4. Concordance and discordance.

5. 5. Synchrony and desynchrony

6. 6. The Behavioural Approach Test at the Calgary General Hospital.

Suriclone: A new anxiolytic drug

1. 1. Suriclone, a new psychotherapeutic agent chemically unrelated to benzodiazepines or phenothiazines was assessed in a single-blind dose-ranging study to determine its efficacy and safety in out-patients with generalized anxiety disorder.

2. 2. Suriclone was an effective anxiolytic drug at a dose range between 1.2 mg. and 3.6 mg. per day. The drug, when effective, has a duration of action between 6 and 8 hours. There was no evidence of a rebound phenomenon. There was, however, a rapid return to pre-treatment level of anxiety. Side effects were few, mild and transient.

3. 3. This new molecule may herald an advance in the treatment of these disorders and should be investigated more fully.

Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: A review

Lindefors Nils: Dopaminergic Regulation of Glutamic Acid Decarboxylase mRNA Expression and GABA Release In the Striatum: A Minireview. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 887–903.

1. 1. The majority of neurons in the striatum (caudate-putamen, dorsal striatum; nucleus accumbens, ventral striatum) and in striatal projection regions (the pallidum, the entopeduncular nucleus and substantia nigra reticulata) use γ-aminobuturic acid (GABA) as transmitter and express glutamic acid decarboxylase (GAD; rate limiting enzyme) in the synthesis of GABA. GABA is the major inhibitory transmitter in the mammlian brain.

2. 2. GAD in brain is present as two isoenzymes, GAD₆₅ and GAD₆₇. GAD₆₅ is largely present as an inactive apoenzyme, which can be induced by nerve activity, while most GAD₆₇ is present as a pyridoxal phosphate-bound permanently active holoenzyme. Thus GAD₆₅ and GAD₆₇ seem to provide a dual system for the control of neuronal GABA synthesis.

3. 3. GAD mRNA expression can be visualised and quantified using in situ hybridisation, and GABA release can be quantified using in vivo microdialysis.

4. 4. Different populations of GABA neurons can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia.

5. 5. Inhibition of dopaminergic transmission in the striatum by lesion of dopamine neurons or by neuroleptic treatment is followed by an increased release of GABA and increased expression of GAD₆₇ mRNA in a subpopulation of striatal medium-sized neurons which project to the globus pallidus, and increased striatal GAD enzyme activity.

6. 6. Increased dopaminergic transmission by repeated but not single doses of amphetamine is followed by decreased striatal GABA release and decreased GAD₆₇ mRNA expression in a subpopulation of medium-sized neurons in the striatum.

7. 7. Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence. The majority of these GABA neurons are under inhibitory influence, whereas a small number seem to be stimulated by dopamine.

8. 8. Specific changes in activity in subpopulations of striatal GABA neurons probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment.

CGP 11.952: An experimental benzodiazepine derivative. Effects on cognitive functioning in patients with epilepsy

1. 1. In two open studies using patients with intractable epilepsy, the effects of CGP 11.952, a triazolyl benzophenone, on cognitive functioning were assessed by means of a computerized neuropsychological battery.

2. 2. In the first study CGP 11.952 turned out to have a positive effect on information processing speed, perceptual sensitivity and precisaness of responses.

3. 3. Negative effects were found on reaction time.

4. 4. In the second study this latter effect was less clear.

5. 5. A striking result was the less negative effect on memory consolidation under influence of CGP 11.952 in comparison with other benzodiazepines.

Antidepressant binding: Implications for the mode of action and the biology of depression

1. 1. (³H)Imipramine binding sites in the brain are localized mainly on serotonergic nerve terminals. In the hippocampus of rats with a lesion of serotonergic nerve terminals produced by neonatal administration of 5,7-DHT the depletion of serotonin was paralleled by a decrease in (³H)imipramine recognition sites.

2. 2. (³H)Imipramine recognition sites in brain tissue or platelets are associated with serotonin uptake sites. A significant correlation exists between the potency of a series of antidepressants and other compounds to displace high affinity (³H)imipramine binding and to inhibit the neuronal uptake of serotonin but not of norepinephrine.

3. 3. There is a significant correlation between the ability of drugs to displace (³H)desipramine binding and to inhibit norepinephrine but not serotonin reuptake. (³H)Desipramine recognition sites are located at least in part at noradrenergic nerve terminals since destruction of these terminals by 6-OH-DA results in parallel decrease in (³H)desipramine but not in (³H)imipramine Binding.

4. 4. The high affinity recognition sites of (³H)imipramine and (³H)desipramine in the brain could be physiologically And Pharmacologically relevant regulatory sites associated with neuronal uptake of serotonin and norepinephrine respectively. Treatments which clinically lead to improvement of depression (eg. antidepressants ECT REM sleep deprivation) were shown to “down-regulate” (³H)imipramine binding sites in brain of experimental animals.

5. 5. The density of (³H)imipramine binding sites was shown to be lower in platelets from depressive patients and in brains of suicide victims. It appears that decreased binding of (³H)imipramine to platelets of depressed patients is a promising biological marker of depression although there is no conclusive evidence to indicate whether it is a state- or trait-dependent phenomenon.

Biological markers of depression: Who multi-center studies and future perspective

Tsukasa Koyama and Itaru Yamashita: Biological Markers of Depression; WHO Multi-Center Studies and Future Perspective. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 791–796.

1. 1. Dexamethasone suppresion test (DST), imipramine platelet binding and sleep EEG in depressed patients were studied by the network of WHO Collaborating Centers.

2. 2. DST and sleep EEG indicated abnormalities characteristic to depression, but imipramine platelet binding failed to show difference between depressed and normal subjects.

3. 3. 20 papers related to markers of depression were presented at the 17th Congress of CINP, Kyoto, 1990.

4. 4. They were introduced under 5 headings: 1) DST and its modifications, 2) serotonergic functions, 3) platelet studies, 4) ocular potentials and melatonin, and 5) brain imaging. There are reviewed here.

Diagnosis and pharmacotherapy of conduct disorder

Lavin Michael R. and Arthur Rifkin: Diagnosis and Pharmacotherapy of Conduct Disorders. Prog. Neuro- Psychopharmacol. & Biol. Psychiat. 1993, 17(6): 875–885.

1. 1. There are few double-blind, placebo-controlled studies of the drug treatment of conduct disorders in children and adolescents.

2. 2. The diagnosis of conduct disorders involves a persistent pattern of behavior in which the basic rights of others and standards of society are violated.

3. 3. There is frequent comorbidity associated with conduct disorders including attention-deficit hyperactivity disorder, oppositional defiant disorder, mood disorders and substance abuse.

4. 4. Childhood Conduct disorder is associated with a significant risk for adult psychopathology.

5. 5. A variety of treatment approaches may be employed to combat conduct disorders.

6. 6. The use of neuroleptics, lithium carbonate, stimulants and other agents is reviewed.

The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives).

Mitsukuni Murasaki and Sadanori Miura: The Future of 5-HT_1A Receptor Agonists. (Aryl-Piperazine Derivatives) Prog. Neuro- Psychopharmacol-& Biol Psychiat, 1992, 16(6): 833–845.

1. 1. At present the dominant position among anti-anxiety medications has changed from meprobamate to the benzodiazepine derivatives.

2. 2. In order to avoid benzodiazepine's (BZ) undesirable side effects such as impairment of psycho-motor function, memory impairment, low dose dependence and withdrawal symptoms, a third generation anxiolytic agent, buspirone, the focus of the aryl-piperazine group of anti-anxiety agents, has been introduced recently.

3. 3. Aryl-piperazine derivatives work as 5-HT_1A receptor partial agonists and are known as serotonin normalizers.

4. 4. Therefore, they are expected to have not only an anxiolytic function but also an anti-depressant effect as well.

5. 5. A characteristic of the aryl-piperazine derivatives is that they have no sedative and muscle relaxant effects, and they do not have BZ's undesirable side-effects, especially in regard to withdrawal symptoms. However they have a rather weak anxiolytic action and a slow onset of action.

6. 6. Aryl-piperazine derivatives will not take the place of BZ, but the use of BZ and buspirone as bridge medications, making the most of the strong points of both, can be proposed as a way to compensate for their respective disadvantages.

Comparative study in mice of flunitrazepam vs. diazepam on morphine withdrawal syndrome

1. 1. There is some evidence that benzodiazepine may modify the opioid withdrawal syndrome. We have investigated the effect of two different benzodiazepines, diazepam and flunitrazepam, on the morphine withdrawal syndrome experimentaly induced in mice.

2. 2. Opiate dependence has been induced by administration of morphine s.c. over a period of five days. Two hours after last morphine administration withdrawal syndrome was induced by s.c. injection of naloxone (5mg/kg). The number of jumps, wet-dog-shakes and paw tremor, and the presence or absence of ptosis, diarrhea, teeth chatering and body tremor were evaluated after naloxone injection.

3. 3. All the signs of morphine withdrawal syndrome was antagonized by flunitrazepam and diazepam, only wet-dog-shake was strongly increased by flunitrazepam.