There are many medications available for the treatment of depression.  None of the available research is adequate, since in none of the available research were all patients first placed on simple and healthy vitamins, minerals, and omega-3 fatty acids.  I suggest that all of my depressed patients take a multivitamin with minerals, an extra 800 mcg of folic acid, 2-3 capsules of fish oil or a pound of ocean fish a week, and 800 IU of vitamin D.  These should probably be used by all adults or at least all middle-aged adults and all individuals struggling with depression.  We simply don't know how such simple health measures would affect the outcome of psychiatric medication research.  Research still strongly suggests that anti-depressant medications are still very valuable to many patients, Of course, some patients won't need medications or as much medication if they are on healthy diets, taking reasonable supplements, getting a reasonable amount of exercise, stimulating their brains with bright light, and avoiding substance abuse.  Counseling has also been repeatedly shown of value, although the large majority of patients with severe, chronic depression will need medication.  I personally think that a healthy diet will someday be shown to be important.  A healthy diet eliminates salt, sugar, refined flour, butter, margarine, trans-fats, cheese, and pork and beef fats.  It uses whole grains, fruits, vegetables, nuts, seafood, beans, and optionally poultry without the fatty skin.

My favorite medication strategy is to start with nortriptyline, an inexpensive dual-action tricyclic which does not cause weight gain and has a high safety index.  Dual-action means it increases the activity of both serotonin and norepinepherine.  If this doesn't work, then I might try fluoxetine (generic Prozac), which is a very inexpensive selective serotonin reuptake inhibitor or SSRI.  If this fails, several alternatives are available.  Trazodone is an inexpensive anti-depressant with a strong sleep effect.  I haven't used St. John's wort, but it is an inexpensive herbal treatment that has helped depression in numerous studies.  No other herbal is worth trying.

Bupropion (generic Wellbutrin) is a more expensive anti-depressant which works in a different way, so might work where others have failed.  A second SSRI like sertraline (Zoloft) or citalopram (Celexa) might be worth trying.  Using 5-HTP and/or thyroid as an adjunct to a medicine having partial benefit might help.  Venlafaxine (Effexor) is a useful dual-action anti-depressant.  None of the above medications cause weight gain.  If all of these fail, lithium or an MAO inhibitor antidepressant are worth trying since they too work in very different ways to increase serotonin or norepipherine.  Other medications are available for special cases, for example patients who need to gain weight.  Lamotrigine (Lamictal) might be good for bipolar depression.  Atypical anti-psychotics seem to help some depression, but this has not been as well researched.  If all of these fail, don't forget rTMS and even ECT.

Medications are vitally important for many patients, especially those with chronic or severe depressions.

Frontline Medications: SSRIs, Tricyclics or Something Else

(Below fluoxetine, citalopram, bupropion)

Medications can be of great help in the treatment of depression. However, many cases of situational depression do not need medication and a sizeable percentage of serious depressions do not fully respond to medications.

The SSRI or Selective Serotonin Reuptake Inhibitor family of medicines are currently the most popular type of anti-depressant medications. There are five currently available in the U.S. These have been heavily promoted by the pharmaceutical industry since all but fluoxetine (Prozac) and fluvoxamine (Luvox) are still protected by patents, guaranteeing the drug company large profits. The most popular are sertraline (Zoloft), followed by fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa). Fluvoxamine is much less used, although it is probably just as good for depression. Fluoxetine is falling off in popularity following its loss of patent protection and the large advertising budget that the patent protection afforded, while the others continue to grow in popularity. It has also been the subject of mostly unwarranted controversy.

Thanks to massive drug industry advertising and inaccurate claims that SSRI medications are more effective at treating depression, the percentage of Americans taking psychiatric and anti-depressant medications has more than doubled since 1990. While it is probably true that in 1990 problems with under-medicating were a major concern, today, the issue of over-medicating depression may deserve more attention than it receives.

Hoping to protect their profits, three of the four manufacturers of the most popular SSRIs have come out with slightly different versions, which research finds no more effective than the originals. The makers of Paxil have come out with a slightly longer acting form of paroxetine called Paxil SR. The makers of Prozac have done the same thing, although regular fluoxetine is naturally so long acting a longer acting version is definitely not needed. One study even found that regular generic fluoxetine can be taken as infrequently as twice a week because it is so long acting. The makers of citalopram have also come out with a very slightly different version, escitalopram or Lexapro, by eliminating an inactive isomer. Now, 10 milligrams now works as well as 20 milligrams of the original medicine. Fluoxetine has already lost its patent protection and its wholesale cost has dropped from $348.50 for 100 of the brandnamed 20mg capsules to just $10.95 for 100 of the generic version. The others will soon follow.

Oddly enough, the SSRI medications, which conquered the market their high costs, are absolutely no more effective for the average patient than the much older and less expensive tricyclic medications (TCAs), which were the frontline anti-depressants before the arrival of the SSRIs. In fact, several reviews have found that the traditional tricyclic medications and the newer venlafaxine are better than SSRIs for severe depressions that lead to hospitalization. Imipramine, the most common TCA costs the pharmacist only $5 a month! Of course, since imipramine is a very inexpensive generic, it doesn’t have any advertising budget promoting it.

The SSRI manufacturers have long promoted their medications as being better because the SSRI medications focus specifically on increasing serotonin in the brain by blocking serotonin reuptake. However, it has long been known that norepinephrine also plays an important role in human depression. Imipramine, venlafaxine, and more tricyclines work by blocking both serotonin and norepinephrine reuptake. This is true of other families of anti-depressants as well. For the average patient, an SSRI will work as well as any other anti-depressant and it is a good first medication. However, except of the treatment of obsessive-compulsive disorders, the SSRIs are not superior to several other families of medications.

The one big advantage of the SSRI medications is supposed to be their lower level of side-effects. In fact, SSRI medications don’t have fewer side-effects, just different side effects. In every study designed to show the superiority of SSRI medications over the traditional tricyclics like imipramine, psychiatrists have not used bethanechol to treat the unpleasant anti-cholinergic medication side-effects frequently caused by TCA medication. This has given an unfair advantage to the SSRIs. This advantage was unfair since many of these side-effects, especially the "cotton mouth" or dry mouth side-effect of tricyclics is immediately relieved by bethanechol. Bethanechol is a medication with virtually no side-effects when used to counter anti-cholinergic side-effects. I routinely give my patients to whom I prescribe a TCA some bethanechol samples in case they experience dry mouth, difficulty voiding, or constipation (Everett, 1975). I am certain that if bethanechol had been used in the SSRI vs. TCA studies, that the problem side-effects of the TCAs would have been much, much lower.

Another advantage of the SSRI medications is less weight gain. It is true that many patients on certain TCAs like amitriptyline, and doxepin gained 15 to 25 pounds over a one to two year period of time. However, other TCAs like imipramine and desipramine cause much less weight gain, with imipramine averaging only 5 pounds in long-term studies. Venlafaxine, trazodone, isocarboxazid, and lamotrigine are other options without significant weight gain. Weight gain is, indeed, an issue to which psychiatrists must pay more attention. However, SSRIs are not the only choice.

Some SSRI advocates point out the lower overdose risk of SSRI. By this they mean that SSRIs are less likely to result in death when taken as an overdose than are TCAs. What this overlooks is extensive research showing that the actual suicide rates of patients on SSRIs is no lower than those on TCAs. In fact, only about 1 out of every 100 imipramine overdoses results in death. What the SSRI advocates overlook is that most deaths in suicide attempts are not caused by the anti-depressants themselves, but by other more deadly means. In fact, every large study looking at the issue has found that the rates at which people successfully kill themselves is the same whether they are taking SSRIs, tricyclics or placebo medication. Suicide rates are influenced much more by alcohol and drug abuse, gun availability, anger, and environmental stresses that the type of anti-depressant prescribed has made little difference in actual deaths.

In deciding the best first medication to use, my recommendation is to evaluate each patient individually. SSRI medications are definitely the preferred medication where obsessive compulsive features are prominent. SSRIs may also be the best choice if a parent or family member with depression had been dramatically helped by an SSRI. Of course, if the patient was helped by an SSRI in a previous episode of depression, the SSRI would be preferred unless the financial pressures made imipramine a better choice. Patients with significant weight loss or severe insomnia because of depression might not be good candidates for SSRI treatment, although there is inadequate research on this issue. Patients when severe insomnia and weight loss might be better candidates for imipramine or even amitriptyline. If the person has a bipolar disorder, and especially if he has already suffered a manic episode, bupropion (Wellbutrin) is usually preferred, since it has the least likelihood of inducing a switch from depression straight into mania. SSRIs would be the second choice in such cases. After a heart attack, tricyclics should be avoided on theoretical grounds due to its quinidine-like effects. However, several other anti-depressants not only help the depression, but probably cut the risk of future heart attacks.

However, for the average new patient needing a medication trial for depression, either fluoxetine, imipramine, or trazodone would seem good first medications when all factors are considered. For very severe depressions, imipramine is probably the best first choice in most cases, although venlafaxine or bupropion might be considered or even fluoxetine combined with thyroxine (more on this later).

SSRI medications cause a higher level of anxiety and agitation, insomnia, and sexual difficulties than imipramine. A reported 30% to 70% of SSRI patients will suffer sexual dysfunction while on SSRIs (Gregorian, 2002). While the dry mouth and most anti-cholinergic side-effects of imipramine is easy to treat, the various SSRI side-effects, if they occur, are sometimes more difficult. Most SSRI side-effects will resolve themselves with time. But the pharmaceutical industry’s claim that TCAs have worse side-effects than SSRIs can be simply blamed on the way they do their research.

SSRI and tricyclic anti-depressants appear safe during pregnancy, although it is always best to avoid all medication during depression when possible. One pregnancy option is rTMS. Blood levels are commonly checked on tricyclic medications when these are being given at higher doses. This is usually done just once after the patient has been on a stable dose for about one week.

All tricyclic anti-depressants and trazodone can be taken as a single dose at bedtime. SSRIs, since they tend to keep people awake, can all be taken as a single dose in the morning. Imipramine can be safely started quite quickly for inpatients with 150 mg the first day and 300 mg the second day. This, and adjunctive thyroid (see below), can speed in the treatment of the depression. I like to give my outpatients either free samples of bethanechol or a prescription since over 25% of patients will get at least occasions of dryness of mouth from the imipramine. This is quickly relieved with the bethanechol. Urinary blockage is much less common and more frequent in men. It, too, is quickly relieved with the bethanechol. Bethanechol can also help imipramine constipation or the occasional case of sexual dysfunction.

Anti-Depressants: If the First or Second Don't Work, Keep Trying: In a study of 171 out-patients with major depression and initially treated with fluoxetine for 6 to 12 weeks, if unimproved, patients received a second or third trial of different anti-depressants in an attempt to achieve remission of the depression, i.e., a score of 7 or less on the 17-item Hamilton Rating Scale for Depression. In an intent-to-treat analysis, 66% (113/171) of patients who were treated with second-generation antidepressants and 65% (275/420) of patients who were treated with first-generation antidepressants (tricyclics or MAO inhibitors) eventually achieved remission. Remission rates in the effectiveness study are approximately 20% higher than the rates usually cited in research studies. The usual procedure when comparing treatments is to assess outcome after a single anti-depressant trial. The cumulative high remission rates here suggest antidepressants are effective and should encourage more patients to keep seeking treatment and physicians to develop techniques to improve patient adherence. Remission rates with 3 consecutive antidepressant trials: effectiveness for depressed outpatients. Quitkin FM, et al.  Columbia University. J Clin Psychiatry. 2005 Jun;66(6):670-6. 

Depression: Ask for Medicine and You Shall Receive: Possible Effects of Consumer Ads: Actors were trained and visited 152 family physicians and internists in San Francisco and Rochester, NY either asking for a brandnamed antidepressant (Paxil), asking for an anti-depressant medication without specifying, or making no request. When asked, the actors gave either the symptoms of major depression or an adjustment disorder.  With major depression symptoms, 100% more received medication if they asked for meditation, either the brandnamed or just in general, 57% vs. 31%.  With adjustment disorder (stress, fatigue, etc.), 450% more received the brandnamed medication (55% vs. 10%) and 300% more if asking for medication with specifying (39% vs. 10%). In general, the doctors did a poor job detecting serious depression unless actors asked for medication and doctors considerably over prescribed medication when actors only complained of an adjustment disorder. When patients asked for a specific medication, 60% of the medication prescribed was the brandname requested.  Direct-to-consumer advertising may have competing effects on quality, potentially both averting underuse and promoting overuse. Influence of patients' requests for direct-to-consumer advertised antidepressants: a randomized controlled trial. Kravitz RL, Epstein RM, et al. University of California, Davis. JAMA. 2005 Apr 27;293(16):1995-2002.

Analysis of Meta-Analyses on New vs. Old: 108 meta-analyses of the use of antidepressants in depressive disorders. Defining newer antidepressants as those introduced since the early 1980s, 18 meta-analyses were selected as being informative about their relative efficacy and tolerability in comparative randomised controlled studies (RCTs). Findings with higher confidence include: little difference in efficacy between most new and old antidepressants; superior efficacy of serotonin and noradrenaline re-uptake inhibitors (SNRIs) over selective serotonin re-uptake inhibitors (SSRIs); a slower onset of therapeutic action of fluoxetine over other SSRIs; a different side effect profile of SSRIs to TCAs with superior general tolerability of SSRIs over TCAs; poorer tolerability of fluvoxamine than other SSRIs in a within group comparison; no increased the risk of suicidal acts or ideation in fluoxetine compared with TCAs (or placebo) in low-risk patients. Findings with a lower level of confidence include: greater efficacy of TCAs than SSRIs in in-patients; greater efficacy of amitriptyline than SSRIs; better tolerability of moclobemide than TCAs; no demonstrable difference in tolerability between SSRIs and TCAs in the elderly; no better tolerability of fluvoxamine than TCAs; better tolerability of dothiepin (dosulepin) than SSRIs; better tolerability of sertraline and greater frequency of agitation on fluoxetine than other SSRIs in a within group comparison. In general, the meta-analyses were of uneven quality, as were the studies included, which limits the confidence in many of the results. Generalising from mostly short-term randomised controlled studies to clinical practice requires caution. Anderson, U Manchester, Br Med Bull 2001;57:161-78

Fluozetine(Prozac) No Increase in Suicide: A prospective study of depression found no increase in suicide compared to other anti-depressants. Andrew Leon, Am J Psychiatry 2/99 156:195-201.

Fluoxetine No Withdrawal Syndrome: A DB trial of 395 patients with 60 switched to placebo for 6 weeks found no worsened or new symptoms of withdrawal, possibly due to the long half-life of the drug. Shorter acting SSRIs have been reported to have problems with abrupt discontinuation. David Michelson, J Clin Psychiatry 11/98 59:544-5. 35% paroxetine patients, 80% amitrip, 33% clomipramine and 32% phenelzine and 55% imipramine reported to have withdrawal. Symptoms are GI, headache, lethargy, sweating, sleep disturbance. Usually brief and mild and can be avoided by tapering. J Clin Psych 59:541

Fluoxetine Twice a Week: The half life of fluoxetine is 4-6 days and the half life of its active metabolite norfluoxetine 4-16 days. In a case of a woman stabilized on lithium 600 bid, olanzapine 5 hs, fluoxetine 10 mg/day caused mania. She did well with a reduction to 10 mg twice a week. Megna, Ann Pharmacoth 01;35:45

Recommends 38-62 weeks of Medication Treatment: In a DB PC study by Reimherr of the University of Utah (Am J Psychiatry 9/98 155:1247) randomizing pts to 24 weeks of fluoxetine or 38 weeks or 62 weeks, researchers found relapse higher if medication was stopped at 24 week (49% vs. 26%), and after 38 additional weeks (23% vs 9%) but difference became non-significant after total of 62 weeks (16% vs 10%). 

Few Sex Side-Effects Bupropion, Nefazodone: Bupropion and nefazodone appear to be much less likely to cause sexual dysfunction (<or=10% of patients). Mirtazapine also appears to be associated with a low rate of sexual adverse effects. In a review of research. Antidepressant-induced sexual dysfunction. Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM. Ann Pharmacother 2002 Oct;36(10):1577-89; In another review of DB PC studies covering over 6000 patients, mirtazapine joins venlafaxine and SSRIs in higher sexual adverse effects group (36%-46%). Prevalence of sexual dysfunction among newer antidepressants. Even Bupropion and Nefazodone (28%) had quite a few reports. Bupropion SR (25%) was non-significantly worse than IR (22%). Clayton AH, Pradko JF, et al. J Clin Psychiatry 2002 Apr;63(4):357-66

Sex Side-Effects High with SSRIs: incidence of any type of sexual dysfunction was compared among different drugs: fluoxetine, 57.7% (161/279); sertraline, 62.9% (100/159); fluvoxamine, 62.3% (48/77); paroxetine, 70.7% (147/208); citalopram, 72.7% (48/66); venlafaxine, 67.3% (37/55); mirtazapine, 24.4% (12/49); nefazodone, 8% (4/50); amineptine, 6.9% (2/29); and moclobemide, 3.9% (1/26). Men had a higher frequency of sexual dysfunction (62.4%) than women (56.9%), although women had higher severity. About 40% of patients showed low tolerance of their sexual dysfunction. U Salamanca, Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. Montejo AL, Llorca G, et al. J Clin Psychiatry 2001;62 Suppl 3:10-21

Viagra (Sildenafil) Might Help Antidepressant Induced Problems: A case report of 2 men and 2 women with sexual dysfunction due to SSRI antidepressants were helped by 50 mg or if necessary 100 mg. of sildenafil. George Nurnberg, J Clin Psychiatry 1/99, 60:33-5

Pharmaceutical Trials Eliminate 50% to 85% of Major Depression Patients: 90% of DB trials have minimum depression score cutoffs. A standardized screening of 1500 out-patients found 530 with major depression (MDD) but 50% of these were too mild to qualify for the cut-off of the standard study. This limits the generalizability of current research. Mark Zimmerman, Rhode Island Hospital. APA 5/03. A second report for Brown University says 85% were eliminated out of 378 depressed patients they screened. Bipolar disorder (17.2%), drug or alcohol abuse (15.6%), mild depression (14.0%), medical contraindication (12.9%), and the use of prohibited psychotropic medications (12.4%) were the most common reasons. J Clin Psychiatry. 2003 Sep;64(9):1091-3

Med, Not Cognitive Therapy, Reduces MI Recurrence: After a first attack, depression raises the risk of recurrence two- and fourfold. Study 1,800 patients who had suffered a heart attack in the past month and now met criteria for depression. Half the depressed patients received cognitive psychotherapy, a treatment aimed at reversing self-disparaging thoughts. The other half received "usual care," without psychotherapy. Psychotherapy had no effect on the recurrence of heart attacks or on mortality. Therapy lowered the degree of depression early on; over time, the differences between the treatment and control groups vanished. For ethical reasons, if subjects had severe depression or if they failed to respond to psychotherapy, they were offered medication, principally sertraline. By the end of the study, almost a quarter of the subjects had taken antidepressants for substantial periods of time. Antidepressants were associated with a 30-40% reduction in death or heart attack recurrence. NYT & JAMA 6/22/03

Hippocampal Neurogenesis Mechanism of Action of Anti-Depressants: Blocking the formation of neurons in the hippocampus blocks the behavioral effects of antidepressants in mice. May explain why antidepressants typically take a few weeks to work. Chronic stress, anxiety and depression have been linked to atrophy or loss of hippocampal neurons. Ronald Duman, Yale University, reported that some antidepressants promote hippocampal neurogenesis. Chronically-treated (4 weeks)mice, but not the briefly-treated (5 days) ones, showed a 60 percent boost in a telltale marker of neurogenesis in a key area of the hippocampus. Hen and colleagues selectively targeted the hippocampus with x-rays to kill proliferating cells. This reduced neurogenesis by 85 percent. Antidepressants had no effect on anxiety and depression-related behaviors in the irradiated mice. For example, fluoxetine failed to improve grooming behavior, as it normally does. By knocking out the gene that codes for a key subtype of serotonin receptor (5-HT1A), the researchers created a strain of "knockout" mice that as adults show anxiety-related traits, such as a reluctance to begin eating in a novel environment. While unaffected by chronic treatment with the SSRI fluoxetine, the knockout mice became less anxious after chronic treatment with tricyclic antidepressants, which act via another neurotransmitter, norepinephrine, suggesting an independent molecular pathway. While chronic fluoxetine treatment doubled the number of new hippocampal neurons in normal mice, it had no effect in the knockout mice. The tricyclic imipramine boosted neurogenesis in both types of mice, indicating that the serotonin 1A receptor is required for neurogenesis induced by fluoxetine, but not imipramine. Rene Hen, Columbia University, Science, 8/8/03

Hippocampal Volume Loss Increases in Untreated Depression: An MRI study of 38 female out-patients with recurrent depressions currently in remission found that hippocampal volume decreased as patients reported having had more days of untreated depression. 38 controls. Depressed subjects had 10% less hippocampal grey matter with an average of 5.4 depressive episodes lasting a total of 1341 days of which 517 were treated with anti-depressants. As the number of days of untreated depression increased, those patients had increasingly smaller hippocampal volumes. Hippocampal volume was not affect by age or age of onset. Education had only a trend toward larger volumes. (p=.15). Those depressed patients with few days of untreated depression had near normal volumes while that with 2000 days of untreated depression had volumes almost 20% smaller. p=.0006. The authors conclude antidepressants may be neuroprotective. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry 2003;160:1516-8. Washington Univ.

Withdrawal Mania: Six cases on SSRI (3), vanlafaxine, and TCA-nortriptyline and desipramine (2). Had been tapered over aver. 19 days. Five cases occurred within 3 weeks. All were on lithium during the taper! In one the mania stopped with restart of venlafaxine! The six with out of 73 patients in clinical trials at NIMH.

Switching While Stable OK: 9 pt stable for 8-60 months but wanted d/c due to side-effects (7 SSRI, 1 bupropion, 1 venlafaxine). All changed to another med, 3 changed type, without diff. Posternak, J Aff Disorders 02;69:237

Longer Treatment Reduces Relapse: Meta-analysis of 31 studies with continuation for 1-2 years after recovery found 40% placebo relapse vs. 18% med relapse. Lancet 2003:361;653-661. Wide media coverage of study. John R. Geddes from the University of Oxford and colleagues in Japan and the US.

Nefazodone, SSRI, & Wt Loss: fluoxetine, isocarboxazid, nefazadone, topiramate, and psychostimulants, may cause weight loss. The antipsychotic drugs chlorpromazine, clozapine, and olanzapine are often associated with weight gain. Among antidepressants, amitriptyline and mirtazapine are known to cause weight gain. Psychiatr Serv 2002 Jul;53(7):842-7

Sexual Side-Effects by Anti-Depressant: 1022 Spanish patients interviewed re orgasm, libido, erection, satisfaction, etc. At least one side-effect in fluoxetine, 57.7% (161/279); sertraline, 62.9% (100/159); fluvoxamine, 62.3% (48/77); paroxetine, 70.7% (147/208); citalopram, 72.7% (48/66); venlafaxine, 67.3% (37/55); mirtazapine, 24.4% (12/49); nefazodone, 8% (4/50); amineptine, 6.9% (2/29); and moclobemide, 3.9% (1/26). Men had a higher frequency of sexual dysfunction (62.4%) than women (56.9%), although women had higher severity. About 40% of patients showed low tolerance of their sexual dysfunction. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. J Clin Psychiatry 2001;62 Suppl 3:10-21

Trazodone, SSRIs, Nortriptyline Low OD Potential: British Data 1993-7 Fatal toxicity index (deaths per million prescriptions): Desipramine 201; Amoxapine 93, Dothiepin 53, Tranylcypromine 44, Amitriptyline 38, Imipramine 33, Doxepin 25, Trimipramine 17, Phenelzine 15, Venlafaxine 13, Clomipramine 12, lithium 7, Moclobemide 6, Nortriptyline 5, Maprotiline 5, Trazodone 4, Mianserin 3, Mirtazapine 3, Fluvoxamine 3, Citalopram 2, Sertraline 1, Fluoxetine 1, Paroxetine 1, Nefazodone 0, Isocarboxazid 0 (isocarb small # prescriptions), Reboxetine 0; Anti-depressant overdose accounts for 4-7% of all suicides. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. Buckley NA, McManus PR. BMJ 2002 Dec 7;325(7376):1332-3. Ed: It should be noted that patients on SSRIs kill themselves just as often as those on tricyclics due to the fact that many depressed individuals use much more deadly means of killing themselves, such as hanging, guns, and carbon monoxide, and that these far outweigh the above overdose deaths.

Overdose Toxicity: Of 3,604 single antidepressant deaths between 1975 and 1989, the majority (70.95%) were from amitriptyline or dothiepin. The mean FTI for all drugs for the years 1985-1989 was 35.6; the FTIs for dothiepin, amitriptyline, nortriptyline and tranylcypromine were significantly higher than the mean of all, while those for clomipramine, lofepramine, fluvoxamine, trimipramine, maprotiline, trazodone, mianserin, protriptyline, isocarboxazid and phenelzine were lower. The FTI for the older tricyclic drugs was higher at 43.03 (p < 0.001). The FTI for the monoamine oxidase inhibitors, of 27.03 (p = 0.045), and for all drugs introduced after 1973, of 5.32 (p < 0.001), were each significantly lower than the mean of all drugs. Henry, National Poisons Unit, Guys Hospital, Eur J Med 1992 Oct;1(6):343-8

Why Aren’t Suicides Decreasing: rate of completed suicide has remained quite stable, whereas that of suicide attempts seems to have increased (to the extent it has been studied in defined regions). These are puzzling observations, since depression is the major suicide precursor and and since antidepressants have been increasingly used over the years in the treatment of depression. van Prang, Netherlands, Why has the antidepressant era not shown a significant drop in suicide rates? van Praag HM. Crisis 2002;23(2):77-82

Research Says Suicides are Decreasing: Goran Isacsson, Karolinska Institute said studies in several countries showed suicide rates had declined, sometimes dramatically, since the SSRI drugs were introduced. European Neuropsychopharmacology Congress in Prague 9/23/03 Reuter Health, London. Analysis of suicides in Sweden suggested about 100 deaths were prevented in 1990 following the drugs' Swedish launch. As the use increased, so the suicide rate continued to decline. Another study, of 15,400 Swedish suicides between 1992 and 2000, showed that the suicide rate in people taking antidepressants was 217 per 100,000 person years compared with 477 in people not taking antidepressants. Evidence from other Nordic countries, Australia, and a dramatic decline in suicides among young people in the United States also backed the association between rising anti-depressant use and declining suicide. David Baldwin, Southampton University, UK, said suicide rates had declined in the UK from 6.3 per 1000 person years in the era before treatment to 5.7 in the electroconvulsive therapy (ECT) era, to 3.3 following the introduction of the first antidepressants in the 1960s.

Report Anti-depressant/Anti-Psychotics Don’t Reduce Suicide: Arif Khan, NW Clinical Research Center, Bellevue, WA reviewed 71000 pt in 53 clinical trials finding equal risk of suicide in meds and placebos between 1985 and 2000. Suicide rate in anti-psychotic trials 752/100,000, anti-depressants 655/100,000, general population 11/100,000. Patients on placebo tend to drop out earlier causing some false elevation in comparative rate of suicide for meds not taken into account in study. NIMH Annual Meeting, Psychology Today 9/02

Suicides and Suicide Attempts No Higher With Placebos: In 77 short-term studies with 12,246 patients in dossiers from the Medicines Evaluation Board, the incidence of suicide was 0.1% in both placebo groups and active compound groups. The incidence of attempted suicide was 0.4% in both placebo groups and active compound groups. In eight long-term studies with 1,949 patients, the incidence of suicide in the placebo groups was 0.0% and 0.2% in the active compound groups. Attempted suicide occurred in 0.7% of both placebo groups and active compound groups. Suicide risk in placebo-controlled studies of major depression. Storosum JG, van Zwieten BJ, van den Brink W, Gersons BP, Broekmans AW. Am J Psychiatry 2001 Aug;158(8):1271-5

Suicides & Attempts No Higher with Placebos vs Citalopram or Venlafaxine XR: DB PC studies with either citolopram or venlafaxine XR. 23,201 pt. 32 suicides, 172 attempts. Rates with placebos 0.5 suicides and 6.7 attempts per year, 0.9 with comparator active meds, and 0.6 and 6.3 attempts per year with citalopram or venlafaxine. Symptoms reduction 47.9% with citalopram or venlafaxine, 47.5% with comparator, and 35.5% with placebo. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database. Khan A, Khan SR, Leventhal RM, Brown WA.

Trazodone, Isocarboxazid Safer OD: Of 3,604 single antidepressant deaths between 1975 and 1989, the majority (71%) were from amitriptyline or dothiepin. The mean FTI (Fatal Toxicity Index) for all drugs for the years 1985-1989 was 35.6; the FTIs for dothiepin, amitriptyline, nortriptyline and tranylcypromine were significantly higher than the mean of all, while those for clomipramine, lofepramine, fluvoxamine, trimipramine, maprotiline, trazodone, mianserin, protriptyline, isocarboxazid and phenelzine were lower. Suicide and fatal antidepressant poisoning. Henry JA, Antao CA. Eur J Med 1992 Oct;1(6):343-8

APA 5/17/99: Females tolerate and respond better to SSRI but men slightly better with imipramine. Postmenopausal women tolerate imipramine much better than premenopausal women. Same true with response rate with equal response rate in postmenopausal while SSRI better than impramine in premenopausal. Tricyclics may have added benefits in older patients. Standord monkay research find squirrel monkey very social and stressful if not in groups. Early stressor shows big genetic differences on kids anxiety with sustained cortisol elevation. Recurrent depression and cushing’s disease result in smaller hippocampus due to high cortisol. Monkeys sired by father that showed high anxiety and cortisol had smaller hippocampus, thus genes may determine cortisol response. The stressors themselves did not have a general harmful effect to any great degree. Intermittent maternalseparations were adaptive tho other mothers were around and later when all mothers were removed, this separation helped handle the separation without anxiety. Psychotically depressed patients have smaller hippocampi and poorer verbal declaratory memory. Patients with higher cortisol have more deterioration over time. Smaller hippocampi associated with more recurrences in humans.

Anti-Depressants Protect Heart: 653 cases of first MI and 2990 control subjects participated. After adjustment, using multivariable logistic regression, for age, sex, race, education, exercise, quantity smoked per day, body mass index, aspirin use, family history of MI, number of physician encounters, and history of coronary disease, diabetes, hypertension, or hypercholesterolemia, the odds ratio for MI among current SSRI users compared with nonusers was 0.35 (95% CI 0.18, 0.68; P<0.01). Non-SSRI antidepressant users had a nonsignificant reduction in MI risk with wide confidence intervals (adjusted odds ratio 0.48, CI 0.17, 1.32; P=0.15). However, analysis of this group was limited by the small number. Circulation 2001 Oct 16;104(16):1894-8. U Penn, Sauer, Berlin, Kimmel

Heart Effects Least with Paroxetine & Bupropion: No effect or reductions in QTc produced by sertraline, citalopram, paroxetine and bupropion in multiple studies. Effects of medications on other heart parameters are also briefly reviewed. In particular, the safety of sertraline in post-MI patients and of bupropion in heart disease patients is highlighted. Little information was available on other classes of medications used in psychiatric disorders. What is available concerning lithium, the anticonvulsants and the benzodiazepines indicates little effect on the QTc, although there may be effects on other cardiovascular parameters. Expert Opin Pharmacother 2002 May;3(5):479-98

Anti-Depressants OK in Pregnancy: TCAs & fluoxetine best studied. Other SSRIs appear OK, too. Don’t use MAOIs. Little info for bupropion, nefazodone, or venlafaxine. Try to avoid mood stabilizers or at least use folate with them since valproic acid and carbamazepine have large increased risk for neural tube defects. Avoid anxiolytics. Haloperidol better than low-potency. Little info on atypicals. Recommends continuing anti-psychotic meds. Amer Fam Physician 02;66:629 U Mich

Anti-Depressant Effects on Cognition of Elderly: Review of 18 studies. Says SSRIs and MAOIs no affect. Amitriptyline, mianserin, dothiepin impair attention and nortriptyline, amitriptyline, and maprotiline might impair memory. Nortriptyline effects on cognition primarily at higher blood levels. Netherlands. Effects of antidepressants on cognitive functioning of elderly patients. A review. Knegtering H, Eijck M, Huijsman A. Drugs Aging 1994 Sep;5(3):192-9

Phenelzine, Nortriptyline No Harmful Cognitive Effects on Elderly: DB PC 78 elderly patients. Both equally successful. The effects of mood changes and antidepressants on the cognitive capacity of elderly depressed patients. Georgotas A, McCue RE, Reisberg B, Ferris SH, Nagachandran N, Chang I, Mir P. Int Psychogeriatr 1989 Fall;1(2):135-43

Painful Ejaculation Rx Tamsulosin: Flomax is an antagonist to alpha-1a adrenoceptors in the prostate and used by BPH. Painful ejaculation reported with TCAs, SSRIs, MAOIs, venlafaxine and reboxetine. 2 cases with reboxetine reported treated successfully. Painful ejaculation and urinary hesitancy in association with antidepressant therapy: relief with tamsulosin. Demyttenaere K, Huygens R. Eur Neuropsychopharmacol 2002 Aug;12(4):337-41.

Urinary Hesitancy From Reboxetine Treated with Tamsulosin: Eight males. Relief within 20 minutes in every patients with 0.4mg/d. U Vienna. Successful treatment of reboxetine-induced urinary hesitancy with tamsulosin. Kasper S, Wolf R. Eur Neuropsychopharmacol 2002 Apr;12(2):119-22

Prescribing Practices Not Empirically Based: Despite the lack of evidence of a significant difference in efficacy between older and newer agents, clinicians perceive the newer agents to be more efficacious than the older drugs [tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)] even in the melancholic and anxious depressive subtypes. Similarly, although sexual dysfunction and agitation appear to occur at similar rates with all the SSRIs, fluoxetine was perceived to be most likely to cause these side effects. These findings are significant as they highlight the discrepancy between empirical evidence and clinical practices and suggest that other factors influence clinicians' medication choices in the treatment of depression. MGH, Peterson, Prog Neuropsychopharmacol Biol Psychiatry 2002 Jan;26(1):177-87

New No Better Than Old: The US Agency for Health Care Policy and Research reviewed over 300 DB studies. Participants discontinued newer and older anti-depressants at the same rate but fewer quit SSRIs because of adverse effects. Both newer and older were equally effective. St John’s wort helped mild to moderately severe depression. www.ahcpr.gov/clinic/deprsumm.htm.

Meta-Analyses on New vs. Old: 108 meta-analyses of the use of antidepressants in depressive disorders. Defining newer antidepressants as those introduced since the early 1980s, 18 meta-analyses were selected as being informative about their relative efficacy and tolerability in comparative randomized controlled studies (RCTs). Findings with higher confidence include: little difference in efficacy between most new and old antidepressants; superior efficacy of serotonin and noradrenaline re-uptake inhibitors (SNRIs) over selective serotonin re-uptake inhibitors (SSRIs); a slower onset of therapeutic action of fluoxetine over other SSRIs; a different side effect profile of SSRIs to TCAs with superior general tolerability of SSRIs over TCAs; poorer tolerability of fluvoxamine than other SSRIs in a within group comparison; no increased the risk of suicidal acts or ideation in fluoxetine compared with TCAs (or placebo) in low-risk patients. Findings with a lower level of confidence include: greater efficacy of TCAs than SSRIs in in-patients; greater efficacy of amitriptyline than SSRIs; better tolerability of moclobemide than TCAs; no demonstrable difference in tolerability between SSRIs and TCAs in the elderly; no better tolerability of fluvoxamine than TCAs; better tolerability of dothiepin (dosulepin) than SSRIs; better tolerability of sertraline and greater frequency of agitation on fluoxetine than other SSRIs in a within group comparison. In general, the meta-analyses were of uneven quality, as were the studies included, which limits the confidence in many of the results. Generalizing from mostly short-term randomized controlled studies to clinical practice requires caution. Anderson, U Manchester, Br Med Bull 2001;57:161-78

Urinary Incontinence from Anti-Depressants Treated with Oxybutinin: 3 cases caused by paroxetine, venlafaxine, and sertraline. Two better with d/c and third better with oxybutinin, a urinary antispasmodic at 5 and 2.5mg on alternating days. Votolato, Ohio State, Int Urogyn J 00;11:386

Fractures Increased by New and Old Anti-Depressants: 8,200 women age 65+ not living in nursing homes. 8 percent were taking tranquilizers, 6 percent were on antidepressants, 5 percent were taking narcotics -- like hydrocodone and oxycodone -- and 2 percent were using drugs to control seizures. 15% suffered at least one broken bone away from the spine. Able to take into account many factors known to affect the risk of fractures, including smoking status, physical activity, and the use of estrogen. Tranquilizers didn't seem to be associated with fractures, but mood drugs increased 70%, narcotics and possibly seizure medications had lesser effects. As with the earlier study, the latest work found no difference in fracture risk for women taking either older or newer antidepressants. Dr. Kristine Ensrud, University of Minnesota. 4/28/03 Arch Int Med

Anti-Depressants Upregulate SOD: Superoxide dismutase reduces oxidative stress and may prevent premature aging and neuroal death. Glucocorticoids downregulate. In cell culture study, amitrip, bupropion, dox, and venlafax all uprefulated SOD1 mRNA. Thus, they may be neuroprotective and protect against hippocampal atrophy. Xin-Min, U Saskatchewan, APA 5/99.

Acute Sedating Anti-Depressants or Combining Anti-Depressants and Benzodiazepines Can Affect Driving: In a review of the 10 controlled studies of the impact of various anti-depressants on driving published between 1983 and 2000,