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Although there is strong evidence that light therapy can counter seasonal depression, the efficacy of light therapy as a treatment for major depression is less well established. Also, it looks as if light therapy might be more effective against major depression if it is combined with an antidepressant than if used alone.
In one randomized, controlled trial, for instance, 102 subjects were treated with the SSRI sertraline (50 mg/d). Subjects also received randomized augmentation treatment with 30 minutes of either bright morning (10,000 lux) or dim red (50 lux) light for five weeks. All clinician and self-report measures significantly favored active light augmentation.
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Regarding St. John's wort, trials suggest that it is more effective for mild to moderate depression than for the severe form of the illness.
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Studies have failed to demonstrate the efficacy of acupuncture compared with a control condition for the treatment of major depression.
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And as for folate, its efficacy as a monotherapy for major depressive disorder has yet to be adequately tested. A few trials have found folate to be efficacious and well tolerated, although the best dose and form of folate remain unclear.
Alternative Treatments May Have Some Use in Depression
Психозы (феномены) «гиперчувствительности»
Клинически психозы гиперчувствительности проявляются обострением либо утяжелением симптомов психоза при назначении или смене антипсихотика. Первые клинические описания относятся к началу 60–х годов прошлого века, когда в начале нейролептической терапии на этапе титрации дозы у некоторых больных, преимущественно с органически неполноценной почвой и пожилых, отмечалось резкое усиление психоза. При этом в последующем, при увеличении дозы состояние, как правило, достаточно быстро стабилизировалось. В основе данного феномена – артефактное усиление дофаминовой трансмиссии вследствие гиперчувствительности постсинаптических D2–рецепторов и увеличения их плотности. В последние годы данный клинический феномен регистрировался также при переводе с обычного антипсихотика (антагониста D2–рецепторов) на частичные агонисты дофамина. В данном случае механизм феномена гиперчувствительности несколько иной: высокий аффинитет к данному типу рецепторов и несколько иной профиль активности обусловливает вовлечение новых, ранее не задействованных рецепторов и частичное усиление синаптической трансмиссии в начале терапии.
Конечно, не каждое усиление психотических симптомов после перевода на новый препарат является феноменом гиперчувствительности. Четкая дифференциация с обострением психоза, безусловно, необходима. Одним из опорных признаков может быть тот факт, что риск обострения у стабильных больных низкий в первые 2–3 недели после отмены/перевода и повышается в последующие месяцы. Согласно данным многочисленных обсервационных исследований к факторам риска обострения следует отнести: мужской пол, молодой возраст, наличие органической почвы, зависимостей. Также выше риск обострения у стационарных и недавно стабилизированных пациентов, при резком обрыве терапии, предшествующей терапии высокими дозами АП и клозапином.
Терапевтическая тактика при психозах гиперчувствительности заключается в усилении антипсихотической терапии с быстрым повышением дозы. В то время как при переводе с D2–антагониста на частичный агонист тактика должна быть принципиально иной, с более медленной сменой антипсихотика.
«Ранняя активация» пациента при смене антипсихотика
«Ранняя активация» (РА) – достаточно часто используемое в последнее время определение в литературе. Следует отметить, наряду с «непривычностью» термина для психиатров, также отсутствие четкой клинической дефиниции. В целом под РА понимается развитие у пациента в начале новой антипсихотической терапии избытка энергии, повышенной активности, инсомнии. Традиционно данная симптоматитка рассматривалась как стимулирующий эффект нового препарата, что справедливо воспринимается, как нежелательное явление у психотических больных либо как признаки утяжеления психоза. Вместе с тем клинический феномен РА связан с отменой предшествующего антипсихотика и рассматривается исключительно как эффект отмены. Он связан с прекращением блокады гистаминовых рецепторов 1 типа (H1) и развивается при резкой отмене препаратов, фармакологический профиль которых характеризуется высокой активностью к данному типу рецепторов. К таким препаратам относятся большинство седативных (низкопотентных) антипсихотиков (хлорпромазин, левомепромазин и др.), а также оланзапин и клозапин. Безусловно, в каждом конкретном случае необходим дифференциальный диагноз РА с акатизией, возбуждением и собственно редукцией седативного эффекта.
Терапевтическая тактика заключается в более медленной смене терапии, назначении бензодиазепинов, в том числе в целях профилактики.
Оптимизация тактики смены антипсихотической терапии на модели кветиапина
The first major breakthrough in the treatment of bulimia came with the era of SSRI antidepressant medications. The initial motivation was a perceived link between bulimia and depression, which commonly exist as co-morbid disorders. Serotonin was clearly involved in some way in the mechanisms of active bulimia. In 1997, Prozac became the first drug ever licensed by the FDA for the treatment of bulimia nervosa. The drug’s formal approval was based on clinical studies showing median reductions in binging of as much as 67 per cent for Prozac, compared with 33 per cent for placebo. Vomiting was reduced by 56 per cent, compared to 5 per cent for female placebo users. (About 10 per cent of diagnosed bulimics are males.) While cure is too strong a word, the benefits were quite dramatic in some cases.
What about the roughly 50% of bulimics who do not respond to serotonin-boosting medications? Recent research covered by the science blog Neurotopia points the finger at a long nerve running through the cranium. The tenth cranial nerve, better known as the vagus nerve, branches through the neck, thorax and abdomen, and is involved in breathing, tasting, swallowing, and digestion. Most of the signal traffic carried by the vagus nerve is one way: from the body to the brain. Suspicion fell on the vagus nerve because of its direct involvement with one of bulimia’s most salient traits — the inability to feel normal levels of fullness, or satiety.
Bulimics must eat more at a sitting than non-bulimics in order to feel satisfied. There is evidence of vagus nerve involvement in meal satiation, portion size, and, notably, control of vomiting. Researchers have suggested that bulimics have a relatively insensitive vagus nerve, made even less sensitive by the debilitating cycle of overeating and vomiting. Hence, bulimia patients need greater vagus nerve stimulation in order to stop eating. Interestingly, studies have also shown that people suffering from bulimia have high pain thresholds, compared to non-bulimics.
This dysregulation of the vagus nerve responds to the drug ondansetron, according to recent research published in Physiology & Behavior by Patricia L. Faris and colleagues. The antiemetic effects of ondansetron, which reduce vagus nerve activity by acting on the 5-HT3 serotonin receptor, seem to decrease vomiting while increasing the number of normal meals eaten.
Finally, a third path toward treatment has been sparked by research on opioid receptors. Decreased endogenous opioid activity may also underpin bulimia. A small 2005 study by Johns Hopkins University School of Medicine analyzed the results of brain MRIs on eight bulimic women and eight controls. Bulimics showed decreased opioid receptor binding in the insula, another area of the brain implicated in MRI studies of addiction. The insula has been called the brain’s “gustatory cortex,” and it may be that the repeating cycle of binge and purge activates the opioid system. Opioid receptors are involved in the processing of the reward value of food. This suggests that a drug like naltrexone, which blocks opiate receptors, might also have a role to play in the treatment of bulimia.
Drugs for Bulimia
The actions of S-adenosyl methionine in the central nervous system have been reviewed previously (3, 7, 8). SAMe acts as a major methyl donor for the synthesis of brain amines and maintenance of phospholipid cell membranes. Low levels of SAMe have been reported in the cerebrospinal fluid (CSF) of severely depressed patients. Oral and parenteral administration of SAMe result in a rise in CSF SAMe concentrations, indicating the compound crosses the blood-brain barrier. An increase in SAMe levels has been positively correlated with improvement in depression. SAMe concentrations also appear to rise in patients who respond to other antidepressants such as desipramine. SAMe is produced in the one-carbon cycle involving folate, homocysteine, and vitamin B12 and abnormalities of each of these compounds has been associated with depression. In short, the hypothesis is that abnormalities in the one-carbon cycle may result in low concentrations of SAMe that in turn may limit the synthesis of brain neurotransmitters such as serotonin, norepinephrine, and dopamine. This may directly contribute to depressive symptoms or interfere with or limit the action of other antidepressants. Administration of SAMe may ameliorate these deficiencies or augment antidepressants and facilitate neurotransmission.
In this issue, Papakostas and colleagues (1) report the results of an adjunctive trial of S-adenosyl methionine (SAMe) in 73 patients with major depression who had failed a prior selective serotonin reuptake inhibitor trial at an adequate dose for at least 6 weeks. Patients were randomly assigned to SAMe, with a targeted dose of 800 mg twice a day, or placebo. Both were added to the ongoing antidepressant regimen and continued for 6 weeks. Response according to the primary outcome, the Hamilton Depression Rating Scale (HDRS), was more likely with SAMe (36.1%) than with placebo (17.6%), as was remission (HDRS score ≤ 7): 25.8% versus 11.7%, respectively. Differences were statistically significant and clinically meaningful.
S-Adenosyl Methionine (SAMe) Augmentation in Major Depressive Disorder
Studies of mice and rats infected by T. gondii have shown risky behavior changes, including an attraction to the smell of cat urine that makes them vulnerable to attacks. These findings may have parallels in behavioral changes in people, from schizophrenia to depression and reflex impairment.
Glenn McConkey, a researcher at the University of Leeds in England, reported last year that two genes in T. gondii's DNA contain instructions for the production of an enzyme that makes a brain chemical called dopamine.
"That's somewhat unusual, because other parasites don't have that [dopamine]," said Sarven Sabunciyan, Yolken's colleague at Hopkins. After all, microbes have no brains.
But in higher animals with nervous systems, dopamine is a neurotransmitter with important roles in regulating behavior. Some anti-psychotic drugs used to treat schizophrenia work by blocking dopamine action in the brain.
In May, Hopkins researcher David J. Schretien published a study suggesting that some brain changes and cognitive symptoms in schizophrenics may be caused or worsened by exposure to a herpes simplex virus. A 2005 Czech study found evidence of personality changes in humans infected by another herpes virus called cytomegalovirus. And numerous studies have suggested that flu infections during pregnancy may increase a child's risk of schizophrenia and autism.
Evidence that T. gondii infections may be a cause of schizophrenia, while not yet conclusive, is growing, Yolken said. A review of past studies, published last year by Yolken and Torrey, collected a variety of intriguing correlations. For example: People with schizophrenia have a higher prevalence of T. gondii antibodies in their blood. There are unusually low rates of schizophrenia and toxoplasmosis in countries where cats are rare, and unusually high rates in places where eating uncooked meat is customary. And some adults with toxoplasmosis show psychotic symptoms similar to schizophrenia.
Studies have linked a history of toxoplasmosis with increased rates of other mental changes, too, including bipolar disorders and depression. A 2002 study in the Czech Republic noted slowed reflexes in Toxoplasma-positive people and found links between the infection and increased rates of auto accidents.
Still, the links between schizophrenia and toxoplasmosis are not simple. For example, most people infected with T. gondii never become schizophrenic. And not all schizophrenics have been exposed to toxoplasma.
Yolken believes additional factors, such as an unlucky combination of genes, are probably needed to produce schizophrenia among Toxoplasma-infected people. The parasite's DNA may also be important, since some strains are known to cause more disease.
Studies have also suggested that the timing of the infection — early in life when the brain is developing — and the place in the brain where the cysts settle, may be important, he said.
Yolken said that while T. gondii cysts are invisible to the immune system, they are not totally passive. Inside the cysts, the microbes are alive, sensing their environment, periodically trying to break out, multiply and form more dopamine-making cysts. The flare-ups probably occur when the host's immune system is weakened by illness or stress.
Sabunciyan has reported promising results with a class of anti-malarial drugs, called artemisinins, which appear to be effective at killing T. gondii in tissue cultures. "The next step is to do that in animals," Yolken said.
Yolken, a cat owner who says he has tested positive for Toxoplasma antibodies, said the potential link between Toxoplasma infections and mental illness is no reason for cat owners to panic — they just need to keep some basic hygienic precautions in mind.
Researchers explore link between schizophrenia, cat parasite
Background Depression is associated with cardiovascular (CV) disease, and it has been hypothesized that vitamin (vit)D deficiency may be associated with depression and a contributing factor to excess CV events. Therefore, we evaluated whether there is an association between vitD and incident depression among a CV population.
Methods Patients (N = 7,358) ≥50 years of age, with a CV diagnosis (coronary artery disease, myocardial infarction, congestive heart failure, cerebrovascular accident, transient ischemic accident, atrial fibrillation, or peripheral vascular disease), no prior depression diagnosis, and a measured vitD level were studied. Vitamin D (ng/mL) was stratified into 4 categories: >50 (optimal [O] n = 367), 31 to 50 (normal [N] n = 2,264), 16 to 30 (low [L] n = 3,402), and ≥15 (very low [VL] n = 1,325). Depression was defined by International Classification of Diseases, Ninth Edition, codes: 296.2 to 296.36, 311. VitD categories were evaluated by Cox hazard regression with adjustment by standard CV risk factors.
Results Age averaged 73.1 ± 10.2 years, and 58.8% were female. When compared to O, VL, L, and N were associated with depression (adjusted: VL, hazard ratio [HR] 2.70 [1.35–5.40], P = .005; L, HR 2.15 [1.10–4.21], P = .03; N, HR 1.95 [0.99–3.87], P = .06). This association remained even after adjustment by parathyroid hormone levels. Parathyroid hormone was significantly associated with depression, however, became nonsignificant after adjustment by vitD. Winter (December-February) enhanced this association. Significant associations remained when stratifications were made by age (<65, ≥65), sex, and diabetes, although the associations among those age ≥65 and male sex were enhanced.
Conclusion Among a CV population ≥50 years with no history of depression, vitD levels were shown to be associated with incident depression after vitD draw. This study strengthens the hypothesis of the association between vitD and depression.
Association of Vitamin D Levels with Incident Depression among a General Cardiovascular Population
The symptoms and signs of hyperthyroidism resemble those of primary mental disorders. Overactivity of the adrenergic system caused by hyperthyroidism may explain the similarity between the clinical presentations of hyperthyroidism and mania or anxiety, as well as the precipitating role of hyperthyroidism in the development of mania or anxiety disorder. It may also explain the increased sense of well being often experienced in the early stages of hyperthyroidism.[20,21]
The relationship between hyperthyroidism and depression is less clear. Depression is usually linked to hypothyroidism, not to hyperthyroidism. However, prolonged hyperthyroidism might exhaust noradrenergic transmission and thus contribute to depression. Noradrenergic exhaustion might well occur in patients with hyperthyroidism who have bipolar disorder. In the initial phase of hyperthyroidism, thyroid hormone stimulation of the noradrenergic system may cause mania; later, when noradrenergic neurotransmission is exhausted, it may contribute to depression.[21]
Mental symptoms and disorders secondary to hyperthyroidism should be treated first by restoring euthyroidism. Most mental symptoms, including depression, usually resolve once euthyroidism has been regained. Treatment with beta-adrenergic antagonists alone may quickly relieve many symptoms, including mental symptoms, even if euthyroidism is not restored,[22] providing evidence that overactivity of the adrenergic system is largely responsible for mental symptoms in hyperthyroidism.
Thyroid deficits are frequently observed in bipolar patients, especially in women with the rapid cycling form of the disease.[24] Both subclinical hypothyroidism and subclinical hyperthyroidism increase the risk for Alzheimer's disease, especially in women.[25] However, most hypothyroid patients do not meet the criteria for a mental disorder.
A recent study evaluated brain glucose metabolism during T4 treatment of hypothyroidism. A reduction in depression and cognitive symptoms was associated with restoration of metabolic activity in brain areas that are integral to the regulation of mood and cognition.[26••]
In hypothyroidism, replacement therapy with T4 remains the treatment of choice and resolves most physical and psychological signs and symptoms in most patients. However, some patients do not feel entirely well despite doses of T4 that are usually adequate.[27] In T4-treated patients, it was found that reduced psychological well being is associated with occurrence of polymorphism in the D2 gene,[28••] as well as in the OATP1c1 gene.[29]
Thyroid hormone replacement with a combination of T4 and T3, in comparison with T4 monotherapy, improves mental functioning in some but not all hypothyroid patients,[30,31•] and most of the patients subjectively prefer combined treatment.[32] Two studies have evaluated whether D2 polymorphism is associated with changes in psychological well being after combined T4 and T3 treatment. One underpowered study[33] reported a trend toward improvement. In a second study[28••] involving a very large sample, D2 polymorphism was associated with improvement in psychological well being after T4 and T3 treatment.
Thyroid Disease and Mental Disorders: Cause and Effect or Only comorbidity?
OBJECTIVE: To examine the long-term safety and efficacy of three antipsychotics in early-onset schizophrenia spectrum disorders. METHOD: Patients (8 to 19 years old) who had improved during an 8-week, randomized, double-blind acute trial of olanzapine, risperidone, or molindone (plus benztropine) were eligible to continue on the same medication for up to 44 additional weeks under double-blind conditions. Adjunctive medications were allowed according to defined algorithms. Standardized symptom, safety, and functional assessments were conducted every 4 weeks. RESULTS: Of the 116 youths randomized in the acute trial, 54 entered maintenance treatment (molindone, n = 20; olanzapine, n = 13; risperidone, n = 21). Fourteen (26%) completed 44 weeks of treatment. Adverse effects (n = 15), inadequate efficacy (n = 14), or study nonadherence (n = 8) were the most common reasons for discontinuation. The three treatment arms did not significantly differ in symptom decrease or time to discontinuation. Akathisia was more common with molindone and elevated prolactin concentrations more common with risperidone. Although weight gain and metabolic adverse events had occurred more often with olanzapine and risperidone during the acute trial, no significant between-drug differences emerged in most of these parameters during maintenance treatment. CONCLUSIONS: Only 12% of youths with early-onset schizophrenia spectrum disorders continued on their originally randomized treatment at 52 weeks. No agent demonstrated superior efficacy, and all were associated with side effects, including weight gain. Improved treatments are needed for early-onset schizophrenia spectrum disorders.
Double-Blind Maintenance Safety and Effectiveness Findings From the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) Study.Double-Blind Comparison of First- and Second-Generation Antipsychotics in Early-Onset Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) Study
Bechdorf points out that while rate of development of bipolar disorder in the BAR group (22.7 percent) is more than 100 times that in the general population, “Prospective studies in bigger samples and with longer follow-up periods, better controlled antidepressant use and psychometric measures of conversions are warranted to provide further validity of these criteria.”
Identifying Youth at High Risk for Bipolar Disorder
A small, randomized trial of 2 doses of intranasal insulin showed improvements in memory and functioning and improved CSF biomarker profiles among patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) with treatment over placebo.
The SNIFF-120 trial was a 4-month, randomized, double-blind trial of placebo vs 2 doses of intranasal insulin: 20 or 40 IU daily. One hundred four patients with AD or amnestic MCI participated; patients with diabetes were excluded.
Intranasal Insulin Shows Benefit in Mild Cognitive Impairment and Alzheimer's Disease
