The term neurosteroid was introduced in 1981 (). Evidence that the brain can be a steroidogenic tissue was derived from the finding that substantial quantities of pregnenolone, dehydroepiandrosterone (DHEA), their sulfate esters, and their fatty acid esters were found in the central nervous system (CNS) of mice, rats, pigs, guinea pigs, monkeys, and humans (). Concentration of these steroids in the brain exceeded their plasma concentration and were estimated to be up to 10 times higher, in the order of 10-100 nmol/L (). Furthermore, these steroids appeared to be independent of gonadal and adrenal synthesis because they were present after adrenalectomy and gonadectomy (). In addition, incubation of primary cultures of rat forebrain glial cultures with a precursor of cholesterol led to the formation of cholesterol, pregnenolone, 20-OH-pregnenolone, and progesterone (). These findings from animal studies are supplemented by results from postmortem human brains, in which high concentrations of neurosteroids far exceeding plasma concentrations have also been detected in all CNS regions (). Of special interest from a neuropsychobiological perspective are neuroactive steroids, which include those steroids that act via neuronal Read more [...]

Neurosteroids as anxiolytics

The first evidence that neurosteroids might represent endogenous anxiolytic agents was derived from behavioral changes occurring during pregnancy and PMS and from associated circulating plasma progesterone levels (). The assumption that progesterone and its neuroactive metabolites possess anxiolytic activity through their action at the GABAA receptor complex related to the estrous cycle or pregnancy was further supported by findings from animal models (). Independently from sex-dependent anxiolytic effects, and based on the findings of Majewska et al. (), Crawley et al. () investigated the possibility that THDOC might be an endogenous anxiolytic compound. Intraperitoneally injected THDOC showed anxiolytic activity in two rat models of anxiety tested, separable from the sedative dose range (). After subcutaneous administration of progesterone to rats, D. Bitran et al. () observed anxiolytic effects, which were most probably the result of bioconversion of progesterone to allopregnanolone with subsequent augmentation of GABAA receptor-mediated function. When administered intracerebroventricularly in rats, pregnenolone and allopregnanolone were also shown to display anxiolytic properties, with sedative effects occurring Read more [...]

Possible Clinical Effects of Neurosteroids

The precise role of neurosteroids in cognition as well as neurological and psychiatric disorders is currently under investigation. Although data from human studies are sparse, results obtained from in vitro and in vivo experiments show promising leads for future clinical applications of neurosteroids. Memory In recent years, memory-enhancing properties have been attributed to pregnenolone and pregnenolone sulfate. This effect is probably related to its agonistic function at the NMDA receptor () because NMDA receptor antagonists impair acquisition and/or retention of various memory tasks in rodents (). Studies investigating the effects of intracerebroventricular administration of pregnenolone and pregnenolone sulfate on performances in avoidance tasks in mice () and rats () have so far yielded positive results. Memory-enhancing properties had previously also been described for DHEA and its sulfate in mice (). In addition, lack of progesterone in aged female rats seems to contribute steroid-mediated neuronal degeneration (), pointing toward possible application of neurosteroids in the treatment of dementia disorders. Pain Increased levels of progesterone are known to be associated with decreases in pain sensitivity Read more [...]

Caffeine and Psychotropics

Question. Are there any psychotropics that have a negative interaction with caffeine? Is caffeine bad for people with certain disorders? Answer. There are certainly psychotropics that can interact with caffeine in clinically important ways, though not always in bad ways. First, though, it's important to distinguish two types of drug-drug interactions. In one type of interaction called pharmacokinetic, one drug affects the metabolism of another. That is, one drug alters the way another drug is broken down or eliminated by the body. In the second type of interaction, called pharmacodynamic, one drug affects the way another drug acts on the brain. Caffeine may have both types of interactions with psychotropics. For example, caffeine can increase the excretion of the mood stabilizer, lithium, leading to reduced lithium levels in the blood. In theory, this could reduce the effectiveness of lithium in some patients. On the other hand, caffeine may have a beneficial pharmacodynamic interaction when patients are taking sedative-hypnotics, such as Valium; i.e., caffeine seems to counteract the negative effects of the sedative on the brain, and thus improves cognitive performance. Since caffeine can raise blood pressure Read more [...]

Paxil’s Long Term Effects

Question. Two years ago, I was diagnosed with borderline clinical atypical depression. I've been on 20 mg/day of Paxil ever since. Six months ago, I discontinued the treatment to see the results. Going cold turkey, I experienced severe withdraw symptoms such as intense fatigue, spaceyness, and hangover-like symptoms for three days. My physician says that lifetime treatment may be a reality. What other long-term effects might I experience? Answer. First of all, I think it's important to separate the issue of "withdrawal symptoms" from "long-term effects" of a medication. Many medications - including many used outside of psychiatry - lead to long-term adaptations by the body, on a cellular level. For example, beta blockers - used in the treatment of angina and hypertension - can lead to gradual adaptation of the nervous system, such that suddenly stopping the medicine ("going cold turkey") can lead to serious withdrawal symptoms (rebound angina, or hypertension). This does not imply that beta blockers cause long-term injurious effects - it simply means that your body/nervous system does not like sudden "shocks" of any kind. The withdrawal symptoms that you experienced after suddenly stopping Paxil are well-described Read more [...]

Paxil’s Efficacy

Question. I am a 32-year-old obese male with mild depression and panic disorder. My therapist of three years has suggested that Paxil would be of great benefit to me. I have never taken any psychotropic drugs before, so I don't know what to expect. She feels if I receive the correct dosage, it would help me with my weight problem and help restore my sex drive (over time, of course). What can I expect? Answer. Paxil (paroxetine) is one of a group of antidepressant agents known as SSRIs; they work on a chemical in the brain called serotonin, which is involved in both mood and appetite/carbohydrate craving. SSRIs are clearly helpful in depression and panic disorder, and also help some overweight individuals lose weight. This latter effect may be due to relief of the underlying depression - which results in overeating and decreased physical activity in some cases - or to decreased craving for carbohydrates. Similarly, if an individual has a reduced sex drive ("libido") because of underlying depression - which is very common - antidepressant medication may, indeed, correct this. However, the SSRIs can themselves cause sexual dysfunction in perhaps 15% to 40% of patients; e.g., delayed orgasm or reduced ejaculation. Read more [...]

Explanation of Psychotropic Meds

Question. I'm a school nurse at a special education school for kids with psychiatric and behavioral disorders who are a danger to themselves or others. I give lots of psychotropic meds to kids at school. This year, I'd like to provide some information for teachers and other school staff about the meds our kids are taking. I'd like to briefly touch on how and where in the brain these meds operate, but I don't want to have to give a class in organic chemistry first. Do you have any ideas for resources that might include some good visuals/explanations in plain English? Answer. With the caveat that we still don't fully understand how these psychotropic drugs operate in the brain-or what their long-term effects are in children and adolescents-you might find the book Straight Talk About Psychiatric Medications for Kids, by Timothy Wilens MD, quite helpful. I haven't read it, but I know Dr. Wilens' work, and the contents of the book look promising: e.g., "What Every Parent Should Know about Psychiatric Medications for Children"; "The Preliminaries: Building a Foundation of Knowledge", and chapters on the major psychotropic drug groups. As far as illustrations go, Dr. Stephen Stahl has done some very good cartoon-like Read more [...]

Treating Dementia

Question. I am interested in your opinion on the use of Depakote and BuSpar, as opposed to benzodiazepines, in the treatment of agitation and aggression in dementia. What dosages would you suggest? Do you know of any articles reviewing these topics? Answer. There are very few controlled studies bearing on your questions; most of the data are based on case reports and open trials. Typical is the study by Lott, et al., Journal of Neuropsychiatry and Clinical Neurosciences, Summer 1995, pp. 314-319. This was an open study of valproate (375-750 mg/day) in elderly patients with dementia and behavioral agitation; 8 of the 10 patients showed improvement on the valproate, which was well-tolerated. Interestingly, serum levels were in the low range, around 35-50 mcg/ml; some patients were treated with adjunctive psychotropics. Similarly, buspirone (doses of around 30 mg/day ) has been found useful in the treatment of organic-induced aggression and dementia (Stanislav, et al., Journal of Clinical Psychopharmacology, 1994;14:126-130; Colenda, Lancet, 1988;1169). In general, I tend to discourage the use of benzodiazepines (BZDs) for agitated demented patients, since these agents are often (though not always) disinhibiting Read more [...]

The Elderly, Depression & Alcohol

Question. I am writing to see if you have any advice for an 89-year-old female that seems to be falling apart. She's been on anti-depressants for quite a few years and has 24-hour companions helping her at home. Over the last three weeks, she had become unmanageable at home. It got to the point where the doctor recommended a psychiatric evaluation to try and determine the level of depression and dementia. The other factor is she still drinks quite a bit each day (2 to 3 martinis). She is now in a nursing home and called me late this afternoon sounding very, very depressed saying she wants to go home. Her prescribed psychotropic medications include Zoloft, Risperdal, Ativan and Restoril. I know she was on Paxil but don't know the dosage. Her doctor has described her dementia as mild to moderate and her short-term memory is completely shot. Any comments would be greatly appreciated. Answer. I'm assuming, from your narrative, that you are this patient's family member or relative. I can certainly understand your being worried. Of course, I can't offer a diagnostic or treatment opinion on someone I haven't evaluated, but here are some general observations. First, any elderly person who has a fairly rapid deterioration Read more [...]


Question. My son has been diagnosed with paranoid schizophrenia. He came out of acute psychosis with depot Prolixin, then out of deep depression with Paxil. Now he functions fairly well in a group home. When he comes home on the weekend he will be happy one moment, then he will talk of suicide and sleep for long periods. Also, he is dually diagnosed with drug abuse, but is now clean. He still maintains some delusions and has specific hygienic practices that he cannot stop. He admits that he has heard voices arguing since he was a small child. Could he be schizoaffective? He seems to have a mixture of several types of mental illness, although I see him as being higher functioning than most of the others in his group. Answer. I am not in a position to provide a diagnosis of your son, but I will try to give you some general guidance. Schizoaffective disorder (SD) is a rather poorly understood condition, or (more likely) group of conditions. It implies that in addition to the classical symptoms of schizophrenia, such as delusions, hallucinations, disordered thinking and social withdrawal. Individuals with SD usually show periods of either severe depression or mania (a state of extreme agitation, often with euphoric or Read more [...]