in Depression

The Coenzyme NADH

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used in an open label trial as medication in 205 patients suffering from depression with various clinical symptoms. NADH was given orally, intramuscularly or intravenously. The duration of therapy ranged from 5 to 310 days. 93% of the patients exhibited a beneficial clinical effect. An improvement up to 44 with a mean value of 11,5 was observed.

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The Coenzyme Nictinamide Adenine Dinucleotide (NADH)

 

New Trends in Clinical Neuropharmacology Vol. V – n. 314-1991 75
THE COENZYME NICOTINAMIDE ADENINE DINUCLEOTIDE (NADH)
AS BIOLOGICAL ANTIDEPRESSIVE AGENT EXPERIENCE WITH 205 PATIENTS
J.G.D.Birkmayer, W.Birkmayer
Birkmayer Institute for Parkinson Therapy, Vienna, Austria

SUMMARY

The coenzyme nicotinamide adenine dinucleotide (NADH) has been used in an open label trial as medication in 205 patients suffering from depression with various clinical symptoms. NADH was given orally, intramuscularly or intravenously. The duration of therapy ranged from 5 to 310 days. 93% of the patients exhibited a beneficial clinical effect. An improvement up to 44 with a mean value of 11,5 was observed.

KEY WORDS

Depression, NADH, Neurotransmitter, Gatechnolamines

INTRODUCTION

Depression is a neuro-psychiatric disorder which disturbs the behaviour, the physical and mental activity, the emotional effectiveness and many other features which are essential for an active life with a balanced mood. A number of studies revealed that; certain neurotransmitters, in particular Norepinephrine, dopamine, serotonin and their metabolites play a role in the evolving depressive symptoms (10, 11, 14, 20).

Post mortern biochemical analysis of the brain of depressive patients found changes in the neurotransmitter concentration of Norepinephrine, dopamine and serotonin. They were significantly reduced in nucleus ruber, pucleus caudatus and nucleus anygdalae (19). These changes in neurotransmitter concentrations may be responsible for an intraneuronal dysfunction which may be reflected in the variety of clinical symptoms.

It has been observed that many Parkinsonian patients suffer from depressive symptoms (3, 4). There are several reports on the improvement of depression after L-DOPA medication (9, 12, 13).

When treating our Parkinsonian patients with the new medication Nicotinamide adenine dinucleotide (NADH) we observed that the depressive symptoms disappeared. This observation prompted us to study the clinical effect of NADH on patients suffering from psychic depression.

METHODS

In an open label trial 205 patients suffering from depression have been treated with the coenzyme B- Nicotinamide adenine dinucleotide in its reduced form (NADM. Diagnosis and the grade of severity of the depression were established according to the depression scale of Ambrozi – Birkmayer – Neumayer (2).

NADH was given parenterally as well as orally. The parenteral form was applied either intravenously or intramuscularly. NADH (Synonyms: BNADH, reduced DPN, B-DPNH) was obtained from Boehringer Mannheim (Germany). For the i.m. injection 12.5 mg NADH were dissolved in 5ml 0.9 percent sodium chloride, pH 7.4, filtered through a 0.22 mcm Millipore filter and then applied.

For the i.v. application 12.5 mg NADH were dissolved in 5ml 0.9 percent sodium chloride, pH 7.4, filtered through a 0.22 mcm Millipore filter and intravenously infused in 30 minutes.

The oral form consisted of film coated-tablets with 5 mg of NADH in each tablet.

RESULTS

All the patients included in this open label trial are listed in Table 1. The individuals patients have been registered by initials according to the parameters: sex, age, degree of depression before and after therapy, improvement and duration of therapy. 112 (53.6%) of the patients included in the trial were male. The descriptive statistics of all these data are summarized in Table 2. This statistics describe the distribution of the 4 parameters age, duration of therapy, disability before treatment and improvement after treatment.

No Init. Sex Age Disability Improvement Duration of
Before After Therapy (in
days)
001 WJ M 81 60 30 30 14
002 AF M 55 12 2 10 60
003 OB M 73 70 40 30 10
004 SA M 66 60 20 40 8
005 SL F 75 8 4 4 150
006 PO M 71 17 17 0 60
007 AA F 61 14 7 7 12
008 AH M 76 8 2 6 7
009 BM F 66 20 10 10 7
010 BJ F 52 13 1 12 7
011 BH M 71 12 6 6 11
012 BA F 71 40 20 20 8
013 BM F 77 25 15 10 14
014 BL F 86 18 6 12 12
015 GM F 78 24 11 13 8
016 CL M 77 40 10 30 20
017 EE M 47 5 3 2 7
018 EW M 76 70 50 20 28
019 FA F 76 20 3 17 310
020 FR M 61 20 20 0 90
021 GR M 74 60 29 31 62
022 GC F 72 18 16 2 28
023 HT F 72 21 16 5 14
024 HM F 75 23 10 13 35
025 HL F 70 75 45 30 20
026 HF M 74 66 66 0 90
027 KC F 72 70 35 35 140
028 TM F 57 20 9 11 10
029 KH M 78 16 12 4 12
030 PB M 61 60 30 30 70
031 RL F 79 26 17 9 14
032 NK M 78 36 15 21 14
033 NO M 53 15 5 10 10

No. Init. Sex Age Disability
Before After Improvement Duration of Therapy (in Days)
034 MP F 68 21 11 10 9
035 MD M 77 20 10 10 14
036 MK M 62 20 6 14 77
037 MA M 75 32 20 12 14
038 LA F 77 5 1 4 14
039 LK M 74 20 10 10 14
040 HF M 60 40 8 32 90
041 HH M 62 55 25 30 12
042 SE M 78 24 16 8 15
043 SE M 62 11 6 5 14
044 SF M 86 26 21 5 9
045 SI F 80 13 4 9 12
046 SW M 63 50 6 44 74
047 SR M 70 37 15 22 8
048 SA M 64 20 5 15 18
049 VC M 80 25 2 23 14
050 EE M 72 25 10 15 14
051 TM M 61 24 5 19 10
052 NJ M 78 40 30 10 28
053 RO M 78 45 40 5 10
054 SL M 75 10 8 2 10
055 BA M 78 15 5 10 8
056 AR F 58 9 9 0 21
057 BP M 74 15 10 5 8
058 BH F 83 40 20 20 8
059 BE F 79 45 30 15 14
060 BE F 69 30 10 20 15
061 CB M 83 35 20 15 28
062 BE M 71 11 14 -3 14
063 BS F 69 40 35 5 8
064 BA M 69 30 15 15 14
065 BH M 81 22 16 8 10
066 BM F 66 29 10 19 14
067 BH M 70 40 20 20 14
068 BR M 76 28 18 10 14
069 BG M 67 14 3 11 21
070 BA F 64 35 30 5 10
071 BV F 76 16 6 10 10
072 CA M 51 30 15 15 10
073 CC M 87 50 20 30 9
074 CJ M 64 40 40 0 12
075 DE F 55 14 9 5 15
076 DV F 66 30 15 15 14
077 DA F 65 40 15 25 12
078 DW F 70 35 35 0 18
079 EG F 75 20 15 5 7
080 EH F 73 25 15 10 17
081 EA F 78 4 4 0 10
082 ER M 67 16 4 12 14
083 EW M 84 37 25 12 14
084 EK F 67 10 16 -6 8
085 EE F 83 40 35 5 14
086 FJ F 69 26 7 19 10
087 FK M 74 35 20 15 26
088 FH F 77 30 15 15 13
089 FW M 81 40 30 10 15
090 FH M 83 40 25 15 18
091 FH M 69 26 7 19 10
092 FM F 91 30 25 5 10
093 GH F 71 22 17 5 14
094 GC M 70 30 20 10 5
095 GW M 70 12 7 5 10
096 GF M 75 34 12 22 11
097 GG F 77 34 13 21 15
098 KG M 62 75 70 5 11
099 KB F 56 11 5 6 5
100 KJ F 80 37 23 14 22
101 KW F 82 30 15 15 10
102 KE F 79 30 15 15 8
103 KO M 75 30 17 13 15
104 KH M 83 35 18 17 14
105 KM F 77 33 21 12 16
106 KP M 68 30 15 15 9
107 KG F 71 30 10 20 11
108 KW M 68 8 4 4 9
109 KA F 78 12 4 8 13
110 KB F 53 20 15 5 8
111 KM M 80 35 20 5 8
112 KW M 51 40 30 10 11
113 KJ F 50 4 4 0 12
114 KJ M 78 35 15 20 16
115 KE F 72 8 4 4 13
116 LH F 70 10 6 4 14
117 LK M 75 30 20 10 14
118 LZ F 77 44 42 2 12
119 LR F 76 20 16 4 14
120 LA M 77 5 1 4 13
121 MM F 68 30 20 10 17
122 ME F 72 34 23 11 14
123 MW M 59 11 4 7 13

No. Init. Sex Age Disability
Before After Improvement Duration of Therapy (in Days)
124 MG F 70 35 20 15 34
125 MN M 64 40 30 10 8
126 MB M 68 16 6 10 10
127 ME F 84 44 44 0 14
128 MR M 67 20 10 10 8
129 MG M 80 22 9 13 13
130 HR M 63 22 3 19 13
131 MM F 67 30 26 4 14
132 MW M 42 15 15 0 45
133 NJ F 80 6 4 2 14
134 NW M 79 35 30 5 12
135 NJ M 78 26 19 7 8
136 NE F 72 11 2 9 21
137 OJ F 71 12 5 7 17
138 OM F 73 26 11 15 14
139 OJ M 79 16 8 8 7
140 OT F 78 38 28 10 12
141 OE F 77 20 10 10 12
142 PG M 63 24 9 15 19
143 PM M 83 20 13 7 19
144 PV M 83 13 10 3 8
145 PJ M 77 42 40 2 11
146 PR F 66 9 6 3 15
147 PB F 76 12 9 3 14
148 PJ M 67 32 30 2 12
149 PE M 75 35 23 12 13
150 PN M 76 41 26 15 9
151 RF M 80 30 30 0 21
152 RC F 63 34 20 14 15
153 RA F 81 36 13 23 12
154 RX F 72 20 15 5 11
155 RA F 52 46 30 16 24
156 RJ M 81 12 14 -2 16
157 RK M 69 20 20 0 3
158 RK M 60 41 26 15 26
159 RE M 58 20 15 5 10
160 SJ M 66 36 18 18 14
161 SM F 78 20 16 4 20
162 SK F 77 30 7 23 60
163 SD F 69 36 9 27 15
164 SO M 80 25 11 14 19
165 SW M 69 20 10 10 9
166 SL M 77 25 5 20 10
167 SH M 66 27 27 0 12
168 SM F 78 35 15 20 14
169 SM M 82 37 27 10 12
170 SM F 56 50 15 35 103
171 SA F 77 34 20 14 10
172 SA M 64 6 5 1 10
173 SJ F 76 30 25 5 19
174 SJ M 67 30 10 20 11
175 SJ F 76 30 25 5 19
176 SL F 82 32 15 17 12
177 SM F 60 30 10 20 13
178 SJ F 72 40 14 26 9
179 SP M 62 30 20 10 14
180 SW F 78 28 20 8 30
181 SK M 69 40 25 15 10
182 SJ F 70 38 11 17 12
183 SJ M 58 50 20 30 10
184 SR F 73 7 4 3 10
185 SE F 69 41 35 6 9
186 SH F 56 32 25 7 12
187 SR F 64 48 48 0 24
188 TJ F 71 38 26 12 18
189 TJ M 69 33 20 13 12
190 VH M 73 40 24 16 17
191 VE M 74 42 40 2 21
192 VM F 36 30 15 15 10
193 VR M 61 38 20 18 14
194 VK M 64 40 10 30 20
195 VH M 64 5 3 2 10
196 VK M 78 9 4 5 8
197 WG M 80 45 45 0 21
198 WP M 74 25 15 10 12
199 WE F 68 32 28 4 13
200 WS F 85 40 20 20 8
201 WW M 80 35 22 13 15
202 WR F 64 37 14 13 14
203 WE M 69 40 24 16 14
204 WW F 72 9 5 4 10
205 WE F 88 41 36 5 18
206 WJ F 75 16 18 -2 13
207 WA M 63 26 6 20 7
208 WC M 78 8 4 4 20
209 ZG M 45 30 30 0 8
15 Non responders from 209 = 7,2%

Table 2: Summary statistics

Variable N Mean St.E. St.D. Min Max Median
Age (y) 209 71.1 0.63 9.09 36 91 72
Duration (d) 209 19.5 1.96 28.29 3 10 14
Disability bef 209 28.6 1.00 14.40 4 75 30
Improvement 209 11.5 0.62 8.95 -6 44 10

The age of the patients ranged from 36 to 91 years with a mean value of 71.14+/-9.09. The duration of therapy lasted from 3 to 310 days with a mean value of 19.5+/-28.29 days.
The degree of depression ranged from 4 to 75 with a mean value of 28.6+/-14.40. The overall improvement of the depression was 11.54 – 8.95 with a maximum of 44.

Tables 3 & 4 relate the dependent variable improvement to the independent variables age and disability before treatment. For each combination of the categories of the two variables, two entries are displayed. The first entry is the number of patients in that cell and the second entry is the column percentage.

For example, 16 of the 49 (=32.7%) patients not older than 65 show an improvement less than or equal to
5. Note that among the 209 patients there are some with disability before treatment less than 10. For these little disabled patients, it is not possible, not even theoretically, to show an improvement greater than 10. Analogously, patients with disability before treatment less than 20 cannot show an improvement greater than 20, and so forth. For this reason and because of possible correlations between the independent variables, tables 3 and 4 should be interpreted with caution.

Table III: Improvement versus age

Age
Impr. 65 66-70 71-75 >75 Row Total
5 16
32.7% 12
29.3% 16
40.0% 25
31.6% 69
33.0%
6-10 9
18.4% 9
22.0% 7
17.5% 20
25.3% 45
21.5%
11-15 9
18.4% 8
19.5% 9
22.5% 17
21.5% 43
20.6%
16-20 6
12.2% 7
17.1% 3
7.5% 9
11.4% 25
12.0%
21-25 2
4.1% 1
2.4% 1
2.5% 5
6.3% 9
4.3%
>26 7
14.3% 4
9.8% 4
10.0% 3
3.8% 18
8.6%
Column Total 49
23.4% 41
19.6% 40
19.1% 79
37.8% 209
100.0%

Table IV: Improvement versus disability before treatment

Disability before treatment
Impr. 10 11-20 21-30 31-40 41-50 >50 Row Total
5 20
95.2% 21
42.0% 10
19.2% 8
13.8% 8
47.1% 2
18.2% 69
33.0%
6-10 1
4.8% 21
42.0% 14
26.9% 8
13.8% 1
5.9% 45
21.5%
11-15 7
14.0% 16
30.8% 17
29.3% 3
17.6% 43
20.6%
15-20 1
2.0% 10
19.2% 12
20.7% 1
5.9% 1
9.1% 25
12.0%
5.00 2
3.8% 7
12.1% 9
4.3%
6.00 6
10.3% 4
23.5% 8
72.7% 18
8.6%
Column Total 21
10.0% 50
23.9% 52
24.9% 58
27.8% 17
8.1% 11
5.3% 209
100.0%

For an accurate assessment of the real relationship between age and improvement it is necessary to subtract the effects of the disability before treatment. In doing this we grouped the patients into 2 categories: marked responders (improvement of disability greater than half the original value before therapy) and non-responders or slight responders (improvement less than or equal to half the original value). To avoid classification of an improvement from 5 to 2 or equal to 10 from further analysis. Table 5 summarizes the distribution of the variables age, duration of therapy, disability before treatment, and improvement after treatment for the remaining 188 patients (103 male).

Table V: Summary Statistics

Variable N Mean St.E. St.D. Min Max
Median
Age (y) 188 71.2 0.66 9.10 36 91 72
Duration (d) 188 19.7 2.05 28.13 3 310 14
Disability bef. 188 31.0 0.96 13.16 11 75 30
Improvement 188 12.5 0.65 8.84 -3 44 11

Table 6 relates the response to age separately for various categories of disability before treatment. It turns out that younger patients (<65y) have a better chance to gain a marked improvement than older patients. The last row in table 6 is a statistical artifact due to small N and therefore does not impair this general result.

DISCUSSION

This study confirms and extends our preliminary report on the clinical benefit of NADH for patients suffering from depression (7).

The patients included in our study suffered from depression with various forms of clinical symptoms, in all of which a disturbance in the catecholamines, dopamine, serotonin and Norepinephrine as well as in the metabolites, vanillin mandelicacid and 5- hydroxyindol-acetic acid levels in blood plasma have been observed (G.D. Birkmayer, unpublished results).

According to the guidelines of the Diagnostic and statistical manual of mental disorder (21) one does not distinguish different forms of depression but only the severe of the symptoms.

NADH seems to be effective with all of them. In order to elucidate the mechanism of NADH action we have to look at the biochemical events leading to depression (1). It has been claimed that the balance of neurotransmitters is disturbed and this change is responsible for the clinical symptoms of depression.

Table IV: Percentages of patients with marked improvement

Age
Disab. Bef. <65 66-70 71-75 >75 Row Total
11-20 8/15
53.3% 3/8
37.5% 2/11
18.2% 6/16
37.5% 19/50
38.0%
21-30 5/9
55.6% 4/12
33.3% 4/10
40.0% 6/21
28.6% 19/52
36.5%
31-40 4/11
36.4% 3/14
21.4% 2/9
22.2% 7/24
29.2% 16/58
27.6%
41-50 3/6
50.0% 0/1
0.0% 0/1
0.0% 1/9
11.1% 4/17
23.5%
>50 1/3
33.3% ½ 50.0% ¼ 25.0% 0/2
0.0% 3/11
27.3%

One of the approaches in the treatment of depression is the application of monoaminoxidase (MAO) inhibitors, in order to block the metabolic degradation of the catecholamines thus achieving a higher endogenous concentration. Monoaminoxidase inhibitors such as imipramine and amitryptilin as antidepressive medication (20, 8) have been used for more than 30 years. One of the drawbacks of these monoaminoxidase inhibitors is the blockage of the reuptake of neurotransmitter from the presynaptic neuron. Therefore the neurotransmitter accumulate in the synaptic cleft. This unnatural condition causes clinically side effects. Side-effects indicate always over dosage of the drug. The philosophy of using NADH as antidepressive substance was its potential capacity to stimulate the endogenous biosynthesis of L-DOPA, dopamine, Norepinephrine and other catecholamines, respectively. Previous studies have shown that there is a deficit in the brain of Parkinsonian patients which seems to be responsible for at least some of the symptoms of depression (3,4). As dopamine is synthesized from tyrosine via L-DOPA under the action of tyrosinehydroxylase this particular enzyme plays a central role for biosynthesis of dopamine and noradrenalin (17) due to this also for psychic disorders.

In this context it has been shown that tyrosinehydroxylase is strongly reduced in Parkinsonian patients, not only in the brain, but also in the adrenal medulla (15). This enzyme has 2 cofactors, tetrahydrobiopterin and iron. Tetrahydrobiopterin was found to be reduced in the brain of Parkinsonian patients by more than 50% yielding a decreased tyrosinehydroxylase activity (16). By stimulating the biosynthesis of tetrahydrobiopterin one may achieve an activation of tyrosinehydroxylase which then leads to a higher dopamine production. Tetrahydrobiopterin is synthesized from dihydropterine by an enzyme called dihydropteridinreductase (23). Cofactor of this enzyme is NADH. The working hypothesis was that addition of NADH will trigger tyrosinehydroxylase activation and due to this an increase of L-DOPA and dopamine production. In a study with more than 400 patients we have shown that NADH is able to improve the symptoms of Parkinsonian patients (6). Biochemical analysis showed that the improvement of clinical symptoms was paralleled by an increase of the dopamine metabolites HVA and VMA in the urine which provides indirect evidence that NADH is increasing the endogenous dopamine production (5).

Direct support for our hypothesis have been gained from tissue culture experiments. NADH added to the culture medium increased the production of dopamine in phaeochromocytorna cells up to 6 times.
Furthermore, tyrosine hydroxylase activity was stimulated by NADH to 175% (21).

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